@article{Rapp2026,

title = {A dual catalytic architecture promotes C-2 stereo-inversion of CDP-glucose by the CDP-tyvelose 2-epimerase from Thermodesulfatator atlanticus.},

author = {Christian Rapp and Stevie Overtveldt and Pedro A Sánchez-Murcia and Martin Pfeiffer and Koen Beerens and Magdalena Merkaš and Tea Pavkov-Keller and Tom Desmet and Bernd Nidetzky},

doi = {10.1016/j.jbc.2026.111384},

issn = {1083-351X (Electronic)},

year  = {2026},

date = {2026-03-01},

journal = {The Journal of biological chemistry},

pages = {111384},

abstract = {The CDP-tyvelose 2-epimerase from Thermodesulfatator atlanticus (TaTyvE) catalyzes the C-2 epimerization of CDP-glucose to CDP-mannose. The enzyme uses NAD-dependent oxidation and reduction to achieve C-2 configurational inversion of the substrate. Here, we report the 2.60-Å crystal structure of the tetrameric TaTyvE with NAD(+) bound in all subunits and CDP bound in only one subunit (PDB: 9RL0). Comparison of structures shows that upon binding of CDP, the loop of residues Gly197-Trp207 becomes ordered to close over the binding pocket of the sugar substrate. The enzyme active site of the ternary complex is structurally well preorganized and only moderately affected by the induced-fit conformational change. Combined evidence of molecular dynamics simulations and site-directed mutagenesis supports the suggestion that TaTyvE employs a dual catalytic architecture to control substrate specificity. Asn125, within the TNK segment (Thr124-Asn125-Lys126), promotes sampling of catalytically plausible glucose conformations, whereas the VAM segment (Val83-Ala84-Met85) permits broader conformational flexibility for mannose through backbone contacts. These findings are consistent with a modest ∼12-fold reduction in activity upon substituting Gln205 with alanine, which provides the only side chain contact with mannose outside the VAM segment. In contrast, no activity was detected for the N125A variant. Substrate analogues featuring deoxygenation, stereo-inversion or fluorination at the C-4 were synthesized to examine the role of the sugar C4-OH. MD simulations indicated that the C4-OH interacts with the Val83 backbone and the side chains of Asn125 and Gln205. Wild-type activity was lost completely with CDP-4-deoxy-glucose and was recovered minimally with CDP-4-fluoro-glucose. Additional removal of the hydroxymethyl substituent at the C5 to restrict substrate positioning flexibility resulted in an enhanced reaction rate compared to the parent sugar. Overall, these results highlight the important interplay of structural preorganization and conformational flexibility in TaTyvE for enzyme activity and specificity in the C-2 epimerization of CDP-glucose.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Li2026,

title = {Structural instability impairs function of the UDP-xylose synthase 1 Ile181Asn variant associated with short-stature genetic syndrome in humans.},

author = {Tuo Li and Pedro A Sánchez-Murcia and Bernd Nidetzky},

doi = {10.1002/1873-3468.70277},

issn = {1873-3468 (Electronic)},

year  = {2026},

date = {2026-01-01},

journal = {FEBS letters},

abstract = {Glycosaminoglycan assembly on proteoglycans involves a common tetrasaccharide linker that starts with xylose attached to a serine on the protein. Defective linker biosynthesis caused by a missense mutation of human UDP-xylose synthase (hUXS1) is associated with connective tissue disorders characterized by skeletal abnormality and short stature. The Ile181Asn variant of hUXS1 was reported as inactive in releasing UDP-xylose from UDP-glucuronic acid. Here, we show that Ile181Asn-hUXS1 exhibited catalytic properties similar to the wild-type enzyme but featured a significant decrease in stability, expressed in melting temperature lowered from 48.2 °C to 35.2 °C. At 37 °C, Ile181Asn-hUXS1 was $sim$10-fold less stable and more prone to precipitation than wild-type hUXS1. The loss of function in Ile181Asn-hUXS1 is thus explained by instability, consistent with molecular dynamics simulations predicting structural destabilization. Impact statement The Ile181Asn variant of human UDP-xylose synthase (hUXS1), associated with a short-stature genetic syndrome, has previously been reported as inactive. We show here with experiments and molecular simulations that hUXS1 malfunction arises from structural instability rather than from a catalytic defect.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Vrtalova2026,

title = {Study on the Binding of Five Plant-Derived Secondary Metabolites to G‑Quadruplexes.},

author = {Lucie Vrtalová and Michaela Dobrovolná and Daniel Platero-Rochart and Aleksandra L Ptaszek and Václav Brázda and Pedro A Sánchez-Murcia},

doi = {10.1021/acsomega.5c09032},

issn = {2470-1343 (Electronic)},

year  = {2026},

date = {2026-01-01},

journal = {ACS omega},

volume = {11},

number = {2},

pages = {3096–3107},

abstract = {Chemical targeting of noncanonical secondary structures of DNA and RNA has emerged as a promising approach for therapeutic development. The most promising targets seem to be four-stranded structures in the G-rich regions of the genome, known as G-quadruplexes (G4s), which are associated with important regulatory regions including promoters. In this study, we tested and modeled the binding of five plant-derived secondary metabolites, known for their antiproliferative activity in vitro, to two G4s found in the human genome: the first at the c-Myc proto-oncogene and the second at the human telomere repeat region. Among the tested compounds, brucine exhibited the strongest interaction with both G4 sequences, while ellagic acid demonstrated binding efficacy comparable to that of brucine in the c-Myc sequence. Through molecular dynamics simulations and the Markov state model, we explored the binding modes of these ligands, elucidated the G4 stability in the bound state, and investigated the fluorescence quenching effect of thioflavin T (ThT) upon its displacement. The biological effects of these natural compounds were investigated in human cell lines, and the interaction with G4s was verified experimentally using a fluorescence displacement assay and CD spectroscopy. This study demonstrates the interaction of these natural compounds with the G4 structures and their implications for therapeutic targeting.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Miguel2025,

title = {Reimagining Pt(II) Anticancer Agents: The Role of Ferrocene in Monofunctional Chemotherapeutic Compounds},

author = {Selma Miguel and Javier Ortín-Fernández and Silvia Gómez-Pastor and María Ángeles Moliné and Pedro A Sánchez-Murcia and Inés Corral and Francisco Sanz-Rodríguez and Ana María González-Vadillo},

url = {https://doi.org/10.1021/acs.inorgchem.5c00704},

doi = {10.1021/acs.inorgchem.5c00704},

issn = {0020-1669},

year  = {2025},

date = {2025-06-01},

journal = {Inorganic Chemistry},

volume = {64},

number = {23},

pages = {11497–11509},

publisher = {American Chemical Society},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Mandl2025,

title = {A new view of missense mutations in α-mannosidosis using molecular dynamics conformational ensembles},

author = {Špela Mandl and Bruno Di Geronimo and Santiago Alonso-Gil and Christoph Grininger and Gibu George and Ulrika Ferstl and Sereina Annik Herzog and Bojan Žagrović and Christoph Nusshold and Tea Pavkov-Keller and Pedro A Sánchez-Murcia},

url = {https://doi.org/10.1002/pro.70080},

doi = {https://doi.org/10.1002/pro.70080},

issn = {0961-8368},

year  = {2025},

date = {2025-04-01},

journal = {Protein Science},

volume = {34},

number = {4},

issue = {4},

pages = {e70080},

publisher = {John Wiley & Sons, Ltd},

abstract = {Abstract The mutation of remote positions on enzyme scaffolds and how these residue changes can affect enzyme catalysis is still far from being fully understood. One paradigmatic example is the group of lysosomal storage disorders, where the enzyme activity of a lysosomal enzyme is abolished or severely reduced. In this work, we analyze molecular dynamics simulation conformational ensembles to unveil the molecular features controlling the deleterious effects of the 43 reported missense mutations in the human lysosomal α-mannosidase. Using residue descriptors for protein dynamics, their coupling with the active site, and their impact on protein stability, we have assigned the contribution of each of the missense mutations into protein stability, protein dynamics, and their connectivity with the active site. We demonstrate here that the use of conformational ensembles is a powerful approach not only to better understand missense mutations at the molecular level but also to revisit the missense mutations reported in lysosomal storage disorders in order to aid the treatment of these diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{DiGeronimo2025,

title = {Digging out the Molecular Connections between the Catalytic Mechanism of Human Lysosomal α-Mannosidase and Its Pathophysiology},

author = {Bruno Di Geronimo and Špela Mandl and Santiago Alonso-Gil and Bojan Žagrović and Gilbert Reibnegger and Christoph Nusshold and Pedro A Sánchez-Murcia},

url = {https://doi.org/10.1021/acs.jcim.4c02229},

doi = {10.1021/acs.jcim.4c02229},

issn = {1549-9596},

year  = {2025},

date = {2025-03-01},

journal = {Journal of Chemical Information and Modeling},

volume = {65},

number = {5},

issue = {5},

pages = {2650–2659},

publisher = {American Chemical Society},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bourgeois2025,

title = {The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI},

author = {Benjamin Bourgeois and Emil Spreitzer and Daniel Platero-Rochart and Margret Paar and Qishun Zhou and Sinem Usluer and Peter L J Keizer and Boudewijn M T Burgering and Pedro A Sánchez-Murcia and Tobias Madl},

url = {https://doi.org/10.1038/s41467-025-60844-9},

doi = {10.1038/s41467-025-60844-9},

issn = {2041-1723},

year  = {2025},

date = {2025-01-01},

journal = {Nature Communications},

volume = {16},

number = {1},

pages = {5672},

abstract = {A central process contributing to the phenotype of aging is cellular senescence. We recently identified the FOXO4 – p53 axis as pivotal in maintaining the viability of senescent cells, and that senescent cells can be targeted selectively with the senolytic peptide FOXO4-DRI. Here, we solve the solution NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain and in complex with FOXO4-DRI. Strikingly, we find that the disordered FOXO4-DRI binds to the disordered p53TAD2 and forms a transiently folded complex. In this complex, both, the FOXO4-derived region and the cationic cell permeability peptide contribute to the interaction. Furthermore, we show that p53 phosphorylation enhances the affinity for both FOXO4 and FOXO4-DRI. Summarizing we provide a detailed characterization of the interaction of p53 with FOXO4 and FOXO4-DRI which is the basis for development of p53 inhibitors to treat diseases linked to cellular senescence such as cancers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sagmeister2024,

title = {The molecular architecture of Lactobacillus S-layer: Assembly and attachment to teichoic acids},

author = {Theo Sagmeister and Nina Gubensäk and Christoph Buhlheller and Christoph Grininger and Markus Eder and Anđela Ðordić and Claudia Millán and Ana Medina and Pedro Alejandro Sánchez Murcia and Francesca Berni and Ulla Hynönen and Djenana Vejzović and Elisabeth Damisch and Natalia Kulminskaya and Lukas Petrowitsch and Monika Oberer and Airi Palva and Nermina Malanović and Jeroen Codée and Walter Keller and Isabel Usón and Tea Pavkov-Keller},

url = {https://doi.org/10.1073/pnas.2401686121},

doi = {10.1073/pnas.2401686121},

year  = {2024},

date = {2024-06-01},

journal = {Proceedings of the National Academy of Sciences},

volume = {121},

number = {24},

pages = {e2401686121},

publisher = {Proceedings of the National Academy of Sciences},

abstract = {S-layer proteins (SLPs) are self-assembling, crystalline proteins coating the cell surfaces of many prokaryotes. This study presents experimental atomic resolution structures of lactobacilli SLPs, deriving functional insight into key probiotic Lactobacillus strains. The structures of SlpA and SlpX proteins highlight the domain swapping critical for SlpX integration, particularly in response to environmental stress. Two binding regions are identified as crucial for attachment of the S-layer to (lipo)teichoic acid. The structure of assembled S-layer provides a foundation for employing (designed) SLPs as a therapeutic agent in the treatment of inflammatory diseases. Additionally, it opens broad avenues for the use of SLPs in vaccine development and in crafting nanostructures with tailored properties, including those designed for targeted drug delivery. S-layers are crystalline arrays found on bacterial and archaeal cells. Lactobacillus is a diverse family of bacteria known especially for potential gut health benefits. This study focuses on the S-layer proteins from Lactobacillus acidophilus and Lactobacillus amylovorus common in the mammalian gut. Atomic resolution structures of Lactobacillus S-layer proteins SlpA and SlpX exhibit domain swapping, and the obtained assembly model of the main S-layer protein SlpA aligns well with prior electron microscopy and mutagenesis data. The S-layer?s pore size suggests a protective role, with charged areas aiding adhesion. A highly similar domain organization and interaction network are observed across the Lactobacillus genus. Interaction studies revealed conserved binding areas specific for attachment to teichoic acids. The structure of the SlpA S-layer and the suggested incorporation of SlpX as well as its interaction with teichoic acids lay the foundation for deciphering its role in immune responses and for developing effective treatments for a variety of infectious and bacteria-mediated inflammation processes, opening opportunities for targeted engineering of the S-layer or lactobacilli bacteria in general.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ferro-Costas2024,

title = {Unraveling the Catalytic Mechanism of β-Cyclodextrin in the Vitamin D Formation},

author = {David Ferro-Costas and Pedro A Sánchez-Murcia and Antonio Fernández-Ramos},

url = {https://doi.org/10.1021/acs.jcim.3c02049},

doi = {10.1021/acs.jcim.3c02049},

issn = {1549-9596},

year  = {2024},

date = {2024-05-01},

journal = {Journal of Chemical Information and Modeling},

volume = {64},

number = {9},

pages = {3865–3873},

publisher = {American Chemical Society},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Platero-Rochart2023,

title = {Prediction of Enzyme Catalysis by Computing Reaction Energy Barriers via Steered QM/MM Molecular Dynamics Simulations and Machine Learning},

author = {Daniel Platero-Rochart and Tatyana Krivobokova and Michael Gastegger and Gilbert Reibnegger and Pedro A Sánchez-Murcia},

url = {https://doi.org/10.1021/acs.jcim.3c00772},

doi = {10.1021/acs.jcim.3c00772},

issn = {1549-9596},

year  = {2023},

date = {2023-07-01},

journal = {Journal of Chemical Information and Modeling},

volume = {63},

issue = {15},

pages = {4623-4632},

publisher = {American Chemical Society},

abstract = {The prediction of enzyme activity is one of the main challenges in catalysis. With computer-aided methods, it is possible to simulate the reaction mechanism at the atomic level. However, these methods are usually expensive if they are to be used on a large scale, as they are needed for protein engineering campaigns. To alleviate this situation, machine learning methods can help in the generation of predictive-decision models. Herein, we test different regression algorithms for the prediction of the reaction energy barrier of the rate-limiting step of the hydrolysis of mono-(2-hydroxyethyl)terephthalic acid by the MHETase ofIdeonella sakaiensis. As a training data set, we use steered quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulation snapshots and their corresponding pulling work values. We have explored three algorithms together with three chemical representations. As an outcome, our trained models are able to predict pulling works along the steered QM/MM MD simulations with a mean absolute error below 3 kcal mol-1 and a score value above 0.90. More challenging is the prediction of the energy maximum with a single geometry. Whereas the use of the initial snapshot of the QM/MM MD trajectory as input geometry yields a very poor prediction of the reaction energy barrier, the use of an intermediate snapshot of the former trajectory brings the score value above 0.40 with a low mean absolute error (ca. 3 kcal mol-1). Altogether, we have faced in this work some initial challenges of the final goal of getting an efficient workflow for the semiautomatic prediction of enzyme-catalyzed energy barriers and catalytic efficiencies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bitter2023,

title = {Enzymatic β-elimination in natural product O- and C-glycoside deglycosylation},

author = {Johannes Bitter and Martin Pfeiffer and Annika J E Borg and Kirill Kuhlmann and Tea Pavkov-Keller and Pedro A Sánchez-Murcia and Bernd Nidetzky},

url = {https://doi.org/10.1038/s41467-023-42750-0},

doi = {10.1038/s41467-023-42750-0},

issn = {2041-1723},

year  = {2023},

date = {2023-01-01},

journal = {Nature Communications},

volume = {14},

number = {1},

pages = {7123},

abstract = {Biological degradation of natural product glycosides involves, alongside hydrolysis, β-elimination for glycosidic bond cleavage. Here, we discover an O-glycoside β-eliminase (OGE) from Agrobacterium tumefaciens that converts the C3-oxidized O-β-d-glucoside of phloretin (a plant-derived flavonoid) into the aglycone and the 2-hydroxy-3-keto-glycal elimination product. While unrelated in sequence, OGE is structurally homologous to, and shows effectively the same Mn2+ active site as, the C-glycoside deglycosylating enzyme (CGE) from a human intestinal bacterium implicated in β-elimination of 3-keto C-β-d-glucosides. We show that CGE catalyzes β-elimination of 3-keto O- and C-β-d-glucosides while OGE is specific for the O-glycoside substrate. Substrate comparisons and mutagenesis for CGE uncover positioning of aglycone for protonic assistance by the enzyme as critically important for C-glycoside cleavage. Collectively, our study suggests convergent evolution of active site for β-elimination of 3-keto O-β-d-glucosides. C-Glycoside cleavage is a specialized feature of this active site which is elicited by substrate through finely tuned enzyme-aglycone interactions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{DeLucio2022,

title = {Identification of 1,2,3-triazolium salt-based inhibitors of Leishmania infantum trypanothione disulfide reductase with enhanced antileishmanial potency in cellulo and increased selectivity.},

author = {Héctor Lucio and Alejandro Revuelto and Alejandra A Carriles and Sonia Castro and Sonia García-González and Juan Carlos García-Soriano and Mercedes Alcón-Calderón and Pedro A Sánchez-Murcia and Juan A Hermoso and Federico Gago and María-José Camarasa and Antonio Jiménez-Ruiz and Sonsoles Velázquez},

doi = {10.1016/j.ejmech.2022.114878},

issn = {1768-3254 (Electronic)},

year  = {2022},

date = {2022-12-01},

journal = {European journal of medicinal chemistry},

volume = {244},

pages = {114878},

abstract = {N-methylation of the triazole moiety present in our recently described triazole-phenyl-thiazole dimerization disruptors of Leishmania infantum trypanothione disulfide reductase (LiTryR) led to a new class of potent inhibitors that target different binding sites on this enzyme. Subtle structural changes among representative library members modified their mechanism of action, switching from models of classical competitive inhibition to time-dependent mixed noncompetitive inhibition. X-ray crystallography and molecular modeling results provided a rationale for this distinct behavior. The remarkable potency and selectivity improvements, particularly against intracellular amastigotes, of the LiTryR dimerization disruptors 4c and 4d reveal that they could be exploited as leishmanicidal agents. Of note, L. infantum promastigotes treated with 4c significantly reduced their low-molecular-weight thiol content, thus providing additional evidence that LiTryR is the main target of this novel compound.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Singer2022,

title = {Unravelling the Turn-On Fluorescence Mechanism of a Fluorescein-Based Probe in GABAA Receptors},

author = {Nadja K Singer and Pedro A Sánchez-Murcia and Margot Ernst and Leticia González},

doi = {https://doi.org/10.1002/anie.202205198},

issn = {1433-7851},

year  = {2022},

date = {2022-07-01},

journal = {Angewandte Chemie International Edition},

volume = {61},

number = {30},

pages = {e202205198},

publisher = {John Wiley & Sons, Ltd},

abstract = {Abstract GABAA (?-aminobutyric acid type A) receptors are ligand-gated ion channels mediating fast inhibitory transmission in the mammalian brain. Here we report the molecular and electronic mechanism governing the turn-on emission of a fluorescein-based imaging probe able to target the human GABAA receptor. Multiscale calculations evidence a drastic conformational change of the probe from folded in solution to extended upon binding to the receptor. Intramolecular ππ-stacking interactions present in the folded probe are responsible for quenching fluorescence in solution. In contrast, unfolding within the GABAA receptor changes the nature of the bright excited state triggering emission. Remarkably, this turn-on effect only manifests for the dianionic prototropic form of the imaging probe, which is found to be the strongest binder to the GABAA receptor. This study is expected to assist the design of new photoactivatable screening tools for allosteric modulators of the GABAA receptor.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Singer2022a,

title = {Unravelling the Turn-On Fluorescence Mechanism of a Fluorescein-Based Probe in GABAA Receptors},

author = {Nadja K Singer and Pedro A Sánchez-Murcia and Margot Ernst and Leticia González},

url = {https://doi.org/10.1002/anie.202205198},

doi = {https://doi.org/10.1002/anie.202205198},

issn = {1433-7851},

year  = {2022},

date = {2022-07-01},

journal = {Angewandte Chemie International Edition},

volume = {61},

number = {30},

pages = {e202205198},

publisher = {John Wiley & Sons, Ltd},

abstract = {Abstract GABAA (?-aminobutyric acid type A) receptors are ligand-gated ion channels mediating fast inhibitory transmission in the mammalian brain. Here we report the molecular and electronic mechanism governing the turn-on emission of a fluorescein-based imaging probe able to target the human GABAA receptor. Multiscale calculations evidence a drastic conformational change of the probe from folded in solution to extended upon binding to the receptor. Intramolecular ππ-stacking interactions present in the folded probe are responsible for quenching fluorescence in solution. In contrast, unfolding within the GABAA receptor changes the nature of the bright excited state triggering emission. Remarkably, this turn-on effect only manifests for the dianionic prototropic form of the imaging probe, which is found to be the strongest binder to the GABAA receptor. This study is expected to assist the design of new photoactivatable screening tools for allosteric modulators of the GABAA receptor.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Gonzlez-Alemn2022,

title = {MDSCAN: RMSD-based HDBSCAN clustering of long molecular dynamics},

author = {Roy González-Alemán and Daniel Platero-Rochart and Alejandro Rodríguez-Serradet and Erix W. Hernández-Rodríguez and Julio Caballero and Fabrice Leclerc and Luis Montero-Cabrera},

doi = {10.1093/bioinformatics/btac666},

issn = {13674811},

year  = {2022},

date = {2022-01-01},

journal = {Bioinformatics},

volume = {38},

issue = {23},

pages = {5191-5198},

publisher = {Oxford University Press},

abstract = {Motivation: The term clustering designates a comprehensive family of unsupervised learning methods allowing to group similar elements into sets called clusters. Geometrical clustering of molecular dynamics (MD) trajectories is a well-established analysis to gain insights into the conformational behavior of simulated systems. However, popular variants collapse when processing relatively long trajectories because of their quadratic memory or time complexity. From the arsenal of clustering algorithms, HDBSCAN stands out as a hierarchical density-based alternative that provides robust differentiation of intimately related elements from noise data. Although a very efficient implementation of this algorithm is available for programming-skilled users (HDBSCAN*), it cannot treat long trajectories under the de facto molecular similarity metric RMSD. Results: Here, we propose MDSCAN, an HDBSCAN-inspired software specifically conceived for non-programmers users to perform memory-efficient RMSD-based clustering of long MD trajectories. Methodological improvements over the original version include the encoding of trajectories as a particular class of vantage-point tree (decreasing time complexity), and a dual-heap approach to construct a quasi-minimum spanning tree (reducing memory complexity). MDSCAN was able to process a trajectory of 1 million frames using the RMSD metric in about 21 h with <8 GB of RAM, a task that would have taken a similar time but more than 32 TB of RAM with the accelerated HDBSCAN* implementation generally used.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Platero-Rochart2022,

title = {RCDPeaks: Memory-efficient density peaks clustering of long molecular dynamics},

author = {Daniel Platero-Rochart and Roy Gonzalez-Aleman and Erix W. Hernandez-Rodriguez and Fabrice Leclerc and Julio Caballero and Luis Montero-Cabrera},

doi = {10.1093/bioinformatics/btac021},

issn = {14602059},

year  = {2022},

date = {2022-01-01},

journal = {Bioinformatics},

volume = {38},

issue = {7},

pages = {1863-1869},

publisher = {Oxford University Press},

abstract = {Motivation: Density Peaks is a widely spread clustering algorithm that has been previously applied to Molecular Dynamics (MD) simulations. Its conception of cluster centers as elements displaying both a high density of neighbors and a large distance to other elements of high density, particularly fits the nature of a geometrical converged MD simulation. Despite its theoretical convenience, implementations of Density Peaks carry a quadratic memory complexity that only permits the analysis of relatively short trajectories. Results: Here, we describe DP+, an exact novel implementation of Density Peaks that drastically reduces the RAM consumption in comparison to the scarcely available alternatives designed for MD. Based on DP+, we developed RCDPeaks, a refined variant of the original Density Peaks algorithm. Through the use of DP+, RCDPeaks was able to cluster a one-million frames trajectory using less than 4.5 GB of RAM, a task that would have taken more than 2 TB and about 3× more time with the fastest and less memory-hunger alternative currently available. Other key features of RCDPeaks include the automatic selection of parameters, the screening of center candidates and the geometrical refining of returned clusters.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Gonzlez-Alemn2022b,

title = {BitQT: a graph-based approach to the quality threshold clustering of molecular dynamics},

author = {Roy González-Alemán and Daniel Platero-Rochart and David Hernández-Castillo and Erix W. Hernández-Rodríguez and Julio Caballero and Fabrice Leclerc and Luis Montero-Cabrera},

doi = {10.1093/bioinformatics/btab595},

issn = {13674811},

year  = {2022},

date = {2022-01-01},

journal = {Bioinformatics},

volume = {38},

issue = {1},

pages = {73-79},

publisher = {Oxford University Press},

abstract = {Motivation: Classical Molecular Dynamics (MD) is a standard computational approach to model time-dependent processes at the atomic level. The inherent sparsity of increasingly huge generated trajectories demands clustering algorithms to reduce other post-simulation analysis complexity. The Quality Threshold (QT) variant is an appealing one from the vast number of available clustering methods. It guarantees that all members of a particular cluster will maintain a collective similarity established by a user-defined threshold. Unfortunately, its high computational cost for processing big data limits its application in the molecular simulation field. Results: In this work, we propose a methodological parallel between QT clustering and another well-known algorithm in the field of Graph Theory, the Maximum Clique Problem. Molecular trajectories are represented as graphs whose nodes designate conformations, while unweighted edges indicate mutual similarity between nodes. The use of a binary-encoded RMSD matrix coupled to the exploitation of bitwise operations to extract clusters significantly contributes to reaching a very affordable algorithm compared to the few implementations of QT for MD available in the literature. Our alternative provides results in good agreement with the exact one while strictly preserving the collective similarity of clusters.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{DiGeronimoBAlonso-GilSZagrovicBReibneggerG2022,

title = {Digging out the molecular connections between the active site of human lysosomal alpha-mannosidase and its pathophysiology},

author = {Zagrovic B Alonso-Gil S Di Geronimo B},

year  = {2022},

date = {2022-01-01},

journal = {ChemRxiv},

volume = {preprint},

abstract = {. ; 2022; This content is a preprint and has not been peer-reviewed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Geronimo2022,

title = {Digging out the molecular connections between the active site of human lysosomal alpha-mannosidase and its pathophysiology},

author = {Bruno Di Geronimo and Santiago Alonso-Gil and Bojan Zagrovic and Gilbert Reibnegger and Pedro A. Sánchez-Murcia},

url = {https://doi.org/10.26434/chemrxiv-2022-ts9c6},

year  = {2022},

date = {2022-01-01},

journal = {ChemRxiv},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Spreitzer2022,

title = {FOXO transcription factors differ in their dynamics and intra/intermolecular interactions.},

author = {Emil Spreitzer and T Reid Alderson and Benjamin Bourgeois and Loretta Eggenreich and Hermann Habacher and Greta Brahmersdorfer and Iva Pritišanac and Pedro A Sánchez-Murcia and Tobias Madl},

doi = {10.1016/j.crstbi.2022.04.001},

issn = {2665-928X (Electronic)},

year  = {2022},

date = {2022-01-01},

journal = {Current research in structural biology},

volume = {4},

pages = {118–133},

abstract = {Transcription factors play key roles in orchestrating a plethora of cellular mechanisms and controlling cellular homeostasis. Transcription factors share distinct DNA binding domains, which allows to group them into protein families. Among them, the Forkhead box O (FOXO) family contains transcription factors crucial for cellular homeostasis, longevity and response to stress. The dysregulation of FOXO signaling is linked to drug resistance in cancer therapy or cellular senescence, however, selective drugs targeting FOXOs are limited, thus knowledge about structure and dynamics of FOXO proteins is essential. Here, we provide an extensive study of structure and dynamics of all FOXO family members. We identify residues accounting for different dynamic and structural features. Furthermore, we show that the auto-inhibition of FOXO proteins by their C-terminal trans-activation domain is conserved throughout the family and that these interactions are not only possible intra-, but also inter-molecularly. This indicates a model in which FOXO transcription factors would modulate their activities by interacting mutually.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Cardenas2021,

title = {Deciphering the Chemical Basis of Fluorescence of a Selenium-Labeled Uracil Probe when Bound at the Bacterial Ribosomal A-Site.},

author = {Gustavo Cardenas and Maximilian F S J Menger and Nicolás Ramos-Berdullas and Pedro A Sánchez-Murcia},

doi = {10.1002/chem.202004818},

issn = {1521-3765 (Electronic)},

year  = {2021},

date = {2021-03-01},

journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},

volume = {27},

number = {15},

pages = {4927–4931},

abstract = {We unveil in this work the main factors that govern the turn-on/off fluorescence of a Se-modified uracil probe at the ribosomal RNA A-site. Whereas the constraint into an "in-plane" conformation of the two rings of the fluorophore is the main driver for the observed turn-on fluorescence emission in the presence of the antibiotic paromomycin, the electrostatics of the environment plays a minor role during the emission process. Our computational strategy clearly indicates that, in the absence of paromomycin, the probe prefers conformations that show a dark S(1) electronic state with participation of nπ* electronic transition contributions between the selenium atom and the π-system of the uracil moiety.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{biom11010120,

title = {Molecular Basis of NDT-Mediated Activation of Nucleoside-Based Prodrugs and Application in Suicide Gene Therapy},

author = {Javier Acosta and Elena Pérez and Pedro A Sánchez-Murcia and Cristina Fillat and Jesús Fernández-Lucas},

url = {https://www.mdpi.com/2218-273X/11/1/120},

doi = {10.3390/biom11010120},

issn = {2218-273X},

year  = {2021},

date = {2021-01-01},

journal = {Biomolecules},

volume = {11},

number = {1},

pages = {120},

abstract = {Herein we report the first proof for the application of type II 2′-deoxyribosyltransferase from Lactobacillus delbrueckii (LdNDT) in suicide gene therapy for cancer treatment. To this end, we first confirm the hydrolytic ability of LdNDT over the nucleoside-based prodrugs 2′-deoxy-5-fluorouridine (dFUrd), 2′-deoxy-2-fluoroadenosine (dFAdo), and 2′-deoxy-6-methylpurine riboside (d6MetPRib). Such activity was significantly increased (up to 30-fold) in the presence of an acceptor nucleobase. To shed light on the strong nucleobase dependence for enzymatic activity, different molecular dynamics simulations were carried out. Finally, as a proof of concept, we tested the LdNDT/dFAdo system in human cervical cancer (HeLa) cells. Interestingly, LdNDT/dFAdo showed a pronounced reduction in cellular viability with inhibitory concentrations in the low micromolar range. These results open up future opportunities for the clinical implementation of nucleoside 2′-deoxyribosyltransferases (NDTs) in cancer treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Avagliano2020,

title = {Spiropyran Meets Guanine Quadruplexes: Isomerization Mechanism and DNA Binding Modes of Quinolizidine-Substituted Spiropyran Probes.},

author = {Davide Avagliano and Pedro A Sánchez-Murcia and Leticia González},

doi = {10.1002/chem.202001586},

issn = {1521-3765 (Electronic)},

year  = {2020},

date = {2020-10-01},

journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},

volume = {26},

number = {57},

pages = {13039–13045},

abstract = {The recent delivery of a fluorescent quinolizidine-substituted spiropyran, which is able to switch in vivo and bind to guanine quadruplexes (G4) at physiological pH values, urged us to elucidate its molecular switching and binding mechanism. Combining multiscale dynamical studies and accurate quantum chemical calculations, we show that, both in water and in the G4 environment, the switching of the spiropyran ring is not promoted by an initial protonation event-as expected by the effect of low pH solutions-but that the deprotonated merocyanine form is an intermediate of the reaction leading to the protonated open species. Additionally, we investigate the binding of both deprotonated and protonated open forms of merocyanine to c-MYC G4s. Both species bind to G4s albeit with different hydrogen-bond patterns and provide distinct rotamers around the exocyclic double bond of the merocyanine forms. Altogether, our study sheds light on the pharmacophoric points for the binding of these probes to DNA, and thereby, contributes to future developments of new G4 binders of the remarkable family of quinolizidine-substituted spiropyrans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Avagliano2019a,

title = {Directional and regioselective hole injection of spiropyran photoswitches intercalated into A/T-duplex DNA.},

author = {Davide Avagliano and Pedro A Sánchez-Murcia and Leticia González},

doi = {10.1039/c9cp03398j},

issn = {1463-9084 (Electronic)},

year  = {2019},

date = {2019-08-01},

journal = {Physical chemistry chemical physics : PCCP},

volume = {21},

number = {32},

pages = {17971–17977},

abstract = {The electron-hole injection from a family of spiropyran photoswitches into A/T-duplex DNA has been investigated at the molecular level for the first time. Multiscale computations coupled with automatized quantitative wavefunction analysis reveal a pronounced directionality and regioselectivity towards the template strand of the duplex DNA. Our findings suggest that this directional and regioselective photoinduced electron-hole transfer could thus be exploited to tailor the charge transport processes in DNA in specific applications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Revuelto2019,

title = {Pyrrolopyrimidine vs Imidazole-Phenyl-Thiazole Scaffolds in Nonpeptidic Dimerization Inhibitors of Leishmania infantum Trypanothione Reductase.},

author = {Alejandro Revuelto and Marta Ruiz-Santaquiteria and Héctor Lucio and Ana Gamo and Alejandra A Carriles and Kilian Jesús Gutiérrez and Pedro A Sánchez-Murcia and Juan A Hermoso and Federico Gago and María-José Camarasa and Antonio Jiménez-Ruiz and Sonsoles Velázquez},

doi = {10.1021/acsinfecdis.8b00355},

issn = {2373-8227 (Electronic)},

year  = {2019},

date = {2019-06-01},

journal = {ACS infectious diseases},

volume = {5},

number = {6},

pages = {873–891},

abstract = {Disruption of protein-protein interactions of essential oligomeric enzymes by small molecules represents a significant challenge. We recently reported some linear and cyclic peptides derived from an α-helical region present in the homodimeric interface of Leishmania infantum trypanothione reductase ( Li-TryR) that showed potent effects on both dimerization and redox activity of this essential enzyme. Here, we describe our first steps toward the design of nonpeptidic small-molecule Li-TryR dimerization disruptors using a proteomimetic approach. The pyrrolopyrimidine and the 5-6-5 imidazole-phenyl-thiazole α-helix-mimetic scaffolds were suitably decorated with substituents that could mimic three key residues (K, Q, and I) of the linear peptide prototype (PKIIQSVGIS-Nle-K-Nle). Extensive optimization of previously described synthetic methodologies was required. A library of 15 compounds bearing different hydrophobic alkyl and aromatic substituents was synthesized. The imidazole-phenyl-thiazole-based analogues outperformed the pyrrolopyrimidine-based derivatives in both inhibiting the enzyme and killing extracellular and intracellular parasites in cell culture. The most active imidazole-phenyl-thiazole compounds 3e and 3f inhibit Li-TryR and prevent growth of the parasites at low micromolar concentrations similar to those required by the peptide prototype. The intrinsic fluorescence of these compounds inside the parasites visually demonstrates their good permeability in comparison with previous peptide-based Li-TryR dimerization disruptors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Avagliano2019,

title = {DNA-binding mechanism of spiropyran photoswitches: The role of electrostatics},

author = {Davide Avagliano and Pedro A. Sánchez-Murcia and Leticia González},

doi = {10.1039/c8cp07508e},

issn = {14639076},

year  = {2019},

date = {2019-01-01},

journal = {Physical Chemistry Chemical Physics},

volume = {21},

number = {17},

pages = {8614–8618},

abstract = {The binding mechanism of the protonated open form of three spiropyran derivatives into a 12-mer (poly-dAT) 2 has been unveiled by means of computational methods. The binding mechanism of the protonated open form of three spiropyran derivatives into a 12-mer (poly-dAT) 2 has been unveiled by means of computational methods. It is found that the electrostatic term in the probe:DNA binding energy, modulates the binding mode, providing new guidelines for the design of spiropyran photoswitches with specific binding modes to DNA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bernardo-Garcia2019,

title = {Cold-induced aldimine bond cleavage by Tris in Bacillus subtilis alanine racemase},

author = {Noelia Bernardo-García and Pedro A Sánchez-Murcia and Akbar Espaillat and Siseth Martínez-Caballero and Felipe Cava and Juan A Hermoso and Federico Gago},

doi = {10.1039/C9OB00223E},

year  = {2019},

date = {2019-01-01},

journal = {Org. Biomol. Chem.},

volume = {17},

number = {17},

pages = {4350–4358},

publisher = {The Royal Society of Chemistry},

abstract = {Pyridoxal 5′-phosphate (PLP) is a versatile cofactor involved in a large variety of enzymatic processes. Most of PLP-catalysed reactions, such as those of alanine racemases (AlaRs), present a common resting state in which the PLP is covalently bound to an active-site lysine to form an internal aldimine. The crystal structure of BsAlaR grown in the presence of Tris lacks this covalent linkage and the PLP cofactor appears deformylated. However, loss of activity in a Tris buffer only occurred after the solution was frozen prior to carrying out the enzymatic assay. This evidence strongly suggests that Tris can access the active site at subzero temperatures and behave as an alternate racemase substrate leading to mechanism-based enzyme inactivation, a hypothesis that is supported by additional X-ray structures and theoretical results from QM/MM calculations. Taken together, our findings highlight a possibly underappreciated role for a common buffer component widely used in biochemical and biophysical experiments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Gavin2019,

title = {Genome mining and characterisation of a novel transaminase with remote stereoselectivity},

author = {D. P. Gavin and F. J. Reen and J. Rocha-Martin and I. Abreu-Castilla and D. F. Woods and A. M. Foley and P. A. Sánchez-Murcia and M. Schwarz and P. O'Neill and A. R. Maguire and F. O'Gara},

doi = {10.1038/s41598-019-56612-7},

issn = {20452322},

year  = {2019},

date = {2019-01-01},

journal = {Scientific Reports},

volume = {9},

number = {1},

pages = {1–15},

abstract = {Microbial enzymes from pristine niches can potentially deliver disruptive opportunities in synthetic routes to Active Pharmaceutical Ingredients and intermediates in the Pharmaceutical Industry. Advances in green chemistry technologies and the importance of stereochemical control, further underscores the application of enzyme-based solutions in chemical synthesis. The rich tapestry of microbial diversity in the oceanic ecosystem encodes a capacity for novel biotransformations arising from the chemical complexity of this largely unexplored bioactive reservoir. Here we report a novel ω-transaminase discovered in a marine sponge Pseudovibrio sp. isolate. Remote stereoselection using a transaminase has been demonstrated for the first time using this novel protein. Application to the resolution of an intermediate in the synthesis of sertraline highlights the synthetic potential of this novel biocatalyst discovered through genomic mining. Integrated chemico-genomics revealed a unique substrate profile, while molecular modelling provided structural insights into this ‘first in class' selectivity at a remote chiral centre.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{C9OB01315F,

title = {Reaction mechanism of nucleoside 2′-deoxyribosyltransferases: free-energy landscape supports an oxocarbenium ion as the reaction intermediate},

author = {Jon Arco and Almudena Perona and Leticia González and Jesús Fernández-Lucas and Federico Gago and Pedro A. Sánchez-Murcia},

url = {http://dx.doi.org/10.1039/C9OB01315F},

doi = {10.1039/C9OB01315F},

issn = {1477-0520},

year  = {2019},

date = {2019-01-01},

journal = {Org. Biomol. Chem.},

volume = {17},

number = {34},

pages = {7891–7899},

publisher = {The Royal Society of Chemistry},

abstract = {Insight into the catalytic mechanism of Lactobacillus leichmannii nucleoside 2′-deoxyribosyltransferase (LlNDT) has been gained by calculating a quantum mechanics–molecular mechanics (QM/MM) free-energy landscape of the reaction within the enzyme active site. Our results support an oxocarbenium species as the reaction intermediate and thus an SN1 reaction mechanism in this family of bacterial enzymes. Our mechanistic proposal is validated by comparing experimental kinetic data on the impact of the single amino acid replacements Tyr7, Glu98 and Met125 with Ala, Asp and Ala/norLeu, respectively, and accounts for the specificity shown by this enzyme on a non-natural substrate. This work broadens our understanding of enzymatic C–N bond cleavage and C–N bond formation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sanchez-Murcia2019,

title = {Unravelling the covalent binding of zampanolide and taccalonolide AJ to a minimalist representation of a human microtubule},

author = {Pedro A. Sánchez-Murcia and Alberto Mills and Álvaro Cortés-Cabrera and Federico Gago},

doi = {10.1007/s10822-019-00208-w},

issn = {15734951},

year  = {2019},

date = {2019-01-01},

journal = {Journal of Computer-Aided Molecular Design},

volume = {33},

number = {7},

pages = {627–644},

publisher = {Springer International Publishing},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ruiz-Santaquiteria2018,

title = {Trypanothione reductase inhibition and anti-leishmanial activity of all-hydrocarbon stapled α-helical peptides with improved proteolytic stability.},

author = {Marta Ruiz-Santaquiteria and Sonia Castro and Miguel A Toro and Héctor Lucio and Kilian Jesús Gutiérrez and Pedro A Sánchez-Murcia and María Ángeles Jiménez and Federico Gago and Antonio Jiménez-Ruiz and María-José Camarasa and Sonsoles Velázquez},

doi = {10.1016/j.ejmech.2018.02.071},

issn = {1768-3254 (Electronic)},

year  = {2018},

date = {2018-04-01},

journal = {European journal of medicinal chemistry},

volume = {149},

pages = {238–247},

abstract = {Trypanothione reductase (TryR) is a well-established target in the search for novel antitrypanosomal and antileishmanial agents. We have previously identified linear and lactam-bridged 13-residue peptides derived from an α-helical region making up part of the dimeric interface of Leishmania infantum TryR (Li-TryR) which prevent trypanothione reduction by disrupting enzyme dimerization. We now show that i,i + 4 side-chain cross-linking with an all-hydrocarbon staple stabilizes the helical structure of these peptides and significantly improves their resistance to protease cleavage relative to previous linear and cyclic lactam analogues. Interestingly, replacement of the amide bridge by the hydrocarbon staple at the same cyclization positions generates derivatives (2 and 3) that similarly inhibit oxidoreductase activity of the enzyme but unexpectedly stabilize the TryR homodimer. The most proteolytically stable peptide 2 covalently linked to oligoarginines displayed potent in vitro leishmanicidal activity against L. infantum parasites.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Torres-Salas2018,

title = {Engineering Erg10 Thiolase from Saccharomyces cerevisiae as a Synthetic Toolkit for the Production of Branched-Chain Alcohols},

author = {Pamela Torres-Salas and Vicente Bernal and Fernando López-Gallego and Javier Martínez-Crespo and Pedro A. Sánchez-Murcia and Victor Barrera and Rocío Morales-Jiménez and Ana García-Sánchez and Aurora Mañas-Fernández and José M. Seoane and Marta Sagrera Polo and Juande D. Miranda and Javier Calvo and Sonia Huertas and José L. Torres and Ana Alcalde-Bascones and Sergio González-Barrera and Federico Gago and Antonio Morreale and María Del Mar González-Barroso},

doi = {10.1021/acs.biochem.7b01186},

issn = {15204995},

year  = {2018},

date = {2018-01-01},

journal = {Biochemistry},

volume = {57},

number = {8},

pages = {1338–1348},

abstract = {Thiolases catalyze the condensation of acyl-CoA thioesters through the Claisen condensation reaction. The best described enzymes usually yield linear condensation products. Using a combined computational/experimental approach, and guided by structural information, we have studied the potential of thiolases to synthesize branched compounds. We have identified a bulky residue located at the active site that blocks proper accommodation of substrates longer than acetyl-CoA. Amino acid replacements at such position exert effects on the activity and product selectivity of the enzymes that are highly dependent on protein scaffold. Among the set of five thiolases studied, Erg10 thiolase from Saccharomyces cerevisiae showed no acetyl-CoA/butyryl-CoA branched condensation activity, but variants in position F293 resulted the most active and selective biocatalysts for this reaction. This is the first time that a thiolase has been engineered to synthesize branched compounds. These novel enzymes enrich the toolbox of c...},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{DeLucio2017,

title = {Improved proteolytic stability and potent activity against Leishmania infantum trypanothione reductase of α/β-peptide foldamers conjugated to cell-penetrating peptides.},

author = {Héctor Lucio and Ana María Gamo and Marta Ruiz-Santaquiteria and Sonia Castro and Pedro A Sánchez-Murcia and Miguel A Toro and Kilian Jesús Gutiérrez and Federico Gago and Antonio Jiménez-Ruiz and María-José Camarasa and Sonsoles Velázquez},

doi = {10.1016/j.ejmech.2017.09.032},

issn = {1768-3254 (Electronic)},

year  = {2017},

date = {2017-11-01},

journal = {European journal of medicinal chemistry},

volume = {140},

pages = {615–623},

abstract = {The objective of the current study was to enhance the proteolytic stability of peptide-based inhibitors that target critical protein-protein interactions at the dimerization interface of Leishmania infantum trypanothione reductase (Li-TryR) using a backbone modification strategy. To achieve this goal we carried out the synthesis, proteolytic stability studies and biological evaluation of a small library of α/β(3)-peptide foldamers of different length (from 9-mers to 13-mers) and different α→β substitution patterns related to prototype linear α-peptides. We show that several 13-residue α/β(3)-peptide foldamers retain inhibitory potency against the enzyme (in both activity and dimerization assays) while they are far less susceptible to proteolytic degradation than an analogous α-peptide. The strong dependence of the binding affinities for Li-TryR on the length of the α,β-peptides is supported by theoretical calculations on conformational ensembles of the resulting complexes. The conjugation of the most proteolytically stable α/β-peptide with oligoarginines results in a molecule with potent activity against L. infantum promastigotes and amastigotes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Oliva2017,

title = {Structure-based domain assignment in Leishmania infantum EndoG: characterization of a pH-dependent regulatory switch and a C-terminal extension that largely dictates DNA substrate preferences},

author = {Cristina Oliva and Pedro A Sánchez-Murcia and Eva Rico and Ana Bravo and Margarita Menéndez and Federico Gago and Antonio Jiménez-Ruiz},

year  = {2017},

date = {2017-01-01},

journal = {Nucleic Acids Research},

volume = {45},

number = {15},

pages = {9030–9045},

publisher = {Oxford University Press},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{CortesCabrera2017,

title = {Making sense of the past: Hyperstability of ancestral thioredoxins explained by free energy simulations},

author = {Álvaro Cortés Cabrera and Pedro A. Sánchez-Murcia and Federico Gago},

doi = {10.1039/c7cp03659k},

issn = {14639076},

year  = {2017},

date = {2017-01-01},

journal = {Physical Chemistry Chemical Physics},

volume = {19},

number = {34},

pages = {23239–23246},

abstract = {Thioredoxin (Trx), a small and globular protein, is present in all kinds of organisms, from Archea to higher mammals. Thioredoxin (Trx), a small and globular protein, is present in all kinds of organisms, from Archea to higher mammals. Throughout evolution, the Trx sequence has undergone subtle modifications to adapt to varying environmental conditions. The high degree of sequence conservation makes Trx very amenable to ancestral protein reconstruction techniques. In this work, we address the study of the structural and energetic determinants of thermostability in E. coli Trx using a dataset of mutations inspired by ancestral reconstruction. We compute, from first principles, the expected contribution of 19 different amino acid substitutions to the stability (ΔΔ G ) and the melting temperature (Δ T m ) of the protein. We also describe the specific changes in structure and protein dynamics responsible for the stabilizing or destabilizing effects of these mutations. Our results point to local and independent changes for most of the variants. Our predictions are accurate enough to substantiate the proposal of new hypotheses regarding evolutionary relationships between mutations, as in the case of T89R, P68A and G74S or K90L and F102A, and reach beyond the initial set to suggest improved variants, such as K90I or K90Y.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Crespo20172,

title = {2′-Deoxyribosyltransferase from Leishmania mexicana, an efficient biocatalyst for one-pot, one-step synthesis of nucleosides from poorly soluble purine bases},

author = {Noé Crespo and Pedro A Sánchez-Murcia and Federico Gago and Janaina Cejudo-Sanches and Miguel Angel Galmes and Jesús Fernández-Lucas and José Miguel Mancheño},

year  = {2017},

date = {2017-01-01},

journal = {Applied microbiology and biotechnology},

volume = {101},

number = {19},

pages = {7187–7200},

publisher = {Springer Berlin Heidelberg},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sanchez-Murcia2017,

title = {Structural rationale for the cross-resistance of tumor cells bearing the A399V variant of elongation factor eEF1A1 to the structurally unrelated didemnin B, ternatin, nannocystin A and ansatrienin B},

author = {Pedro A Sánchez-Murcia and Álvaro Cortés-Cabrera and Federico Gago},

url = {https://doi.org/10.1007/s10822-017-0066-x},

doi = {10.1007/s10822-017-0066-x},

issn = {1573-4951},

year  = {2017},

date = {2017-01-01},

journal = {Journal of Computer-Aided Molecular Design},

volume = {31},

number = {10},

pages = {915–928},

abstract = {At least four classes of structurally distinct natural products with potent antiproliferative activities target the translation elongation factor eEF1A1, which is best known as the G-protein that delivers amino acyl transfer RNAs (aa-tRNAs) to ribosomes during mRNA translation. We present molecular models in atomic detail that provide a common structural basis for the high-affinity binding of didemnin B, ternatin, ansatrienin B and nannocystin A to eEF1A1, as well as a rationale based on molecular dynamics results that accounts for the deleterious effect of replacing alanine 399 with valine. The proposed binding site, at the interface between domains I and III, is eminently hydrophobic and exists only in the GTP-bound conformation. Drug binding at this site is expected to disrupt neither loading of aa-tRNAs nor GTP hydrolysis but would give rise to stabilization of this particular conformational state, in consonance with reported experimental findings. The experimental solution of the three-dimensional structure of mammalian eEF1A1 has proved elusive so far and the highly homologous eEF1A2 from rabbit muscle has been crystallized and solved only as a homodimer in a GDP-bound conformation. Interestingly, in this dimeric structure the large interdomain cavity where the drugs studied are proposed to bind is occupied by a mostly hydrophobic α-helix from domain I of the same monomer. Since binding of this α-helix and any of these drugs to domain III of eEF1A(1/2) is, therefore, mutually exclusive and involves two distinct protein conformations, one intriguing possibility that emerges from our study is that the potent antiproliferative effect of these natural products may arise not only from inhibition of protein synthesis, which is the current dogma, but also from interference with some other non-canonical functions. From this standpoint, this type of drugs could be considered antagonists of eEF1A1/2 oligomerization, a hypothesis that opens up novel areas of research.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Cabrera2017making,

title = {Making sense of the past: hyperstability of ancestral thioredoxins explained by free energy simulations},

author = {Álvaro Cortés Cabrera and Pedro A Sánchez-Murcia and Federico Gago},

year  = {2017},

date = {2017-01-01},

journal = {Physical Chemistry Chemical Physics},

volume = {19},

number = {34},

pages = {23239–23246},

publisher = {Royal Society of Chemistry},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ruiz2017first,

title = {First example of peptides targeting the dimer interface of Leishmania infantum trypanothione reductase with potent in vitro antileishmanial activity},

author = {Marta Ruiz-Santaquiteria and Pedro A Sánchez-Murcia and Miguel A Toro and Héctor Lucio and Kilian Jesús Gutiérrez and Sonia Castro and Filipa A C Carneiro and Federico Gago and Antonio Jiménez-Ruiz and María-José Camarasa and Others},

year  = {2017},

date = {2017-01-01},

journal = {European Journal of Medicinal Chemistry},

volume = {135},

pages = {49–59},

publisher = {Elsevier Masson},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Wang2016,

title = {A novel C, D-spirodioxene taxoid synthesized through an unexpected Pd-mediated ring cyclization},

author = {Shao-Rong Wang and Pedro A Sánchez-Murcia and Federico Gago and Wei-Shuo Fang},

year  = {2016},

date = {2016-01-01},

journal = {Organic & Biomolecular Chemistry},

volume = {14},

number = {1},

pages = {345–352},

publisher = {Royal Society of Chemistry},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bernardo2016structural,

title = {Structural bioinformatics in broad-spectrum racemases: a new path in antimicrobial research},

author = {Noelia Bernardo-García and Pedro Sánchez-Murcia and Federico Gago and Felipe Cava and Juan A Hermoso},

year  = {2016},

date = {2016-01-01},

journal = {Current Organic Chemistry},

volume = {20},

number = {11},

pages = {1222–1231},

publisher = {Bentham Science Publishers},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Filace2016,

title = {Silyl Assistance in the Intramolecular Addition of Pyridyl Radicals onto Pyridines and Quinolines},

author = {Fabiana Filace and Pedro A Sánchez-Murcia and David Suzunza and Adrián Pérez-Redondo and Julio Álvarez-Buílla and Federico Gago and Carolina Burgos},

year  = {2016},

date = {2016-01-01},

journal = {European Journal of Organic Chemistry},

publisher = {Wiley},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Losada2016translation,

title = {Translation elongation factor eEF1A2 is a novel anticancer target for the marine natural product plitidepsin},

author = {Alejandro Losada and María José Muñoz-Alonso and Carolina García and Pedro A Sánchez-Murcia and Juan Fernando Martínez-Leal and Juan Manuel Domínguez and M Pilar Lillo and Federico Gago and Carlos M Galmarini},

year  = {2016},

date = {2016-01-01},

journal = {Scientific reports},

volume = {6},

number = {1},

pages = {1–15},

publisher = {Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Trigili2016structural,

title = {Structural determinants of the dictyostatin chemotype for tubulin binding affinity and antitumor activity against taxane-and epothilone-resistant cancer cells},

author = {Chiara Trigili and Isabel Barasoain and Pedro A Sánchez-Murcia and Katja Bargsten and Mariano Redondo-Horcajo and Aurora Nogales and Nicola M Gardner and Arndt Meyer and Guy J Naylor and Elena Gómez-Rubio and Others},

year  = {2016},

date = {2016-01-01},

journal = {ACS omega},

volume = {1},

number = {6},

pages = {1192–1204},

publisher = {American Chemical Society},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Genes2016pro,

title = {Pro-death activity of a BH3 domain in an aquaporin from the protozoan parasite Leishmania},

author = {Carlos Mario Genes and Héctor De Lucio and Pedro Alejandro Sánchez-Murcia and Federico Gago and Antonio Jiménez-Ruiz},

year  = {2016},

date = {2016-01-01},

journal = {Cell Death & Disease},

volume = {7},

number = {7},

pages = {e2318},

publisher = {Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{MIO2016,

title = {Stepwise simulation of 3, 5-dihydro-5-methylidene-4 H-imidazol-4-one (MIO) biogenesis in histidine ammonia-lyase},

author = {Pedro A Sánchez-Murcia and Juan A Bueren-Calabuig and Marta Camacho-Artacho and Álvaro Cortés-Cabrera and Federico Gago},

year  = {2016},

date = {2016-01-01},

journal = {Biochemistry},

volume = {55},

number = {41},

pages = {5854–5864},

publisher = {American Chemical Society},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Genes2016functional,

title = {A functional BH3 domain in an aquaporin from Leishmania infantum},

author = {Carlos Mario Genes and Héctor Lucio and Víctor M González and Pedro A Sánchez-Murcia and Eva Rico and Federico Gago and Antonio Fasel N. Jiménez-Ruiz},

year  = {2016},

date = {2016-01-01},

journal = {Cell Death Discovery},

volume = {2},

pages = {16043},

publisher = {Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Diez2016,

title = {Molecular interactions and implications of aldose reductase inhibition by PGA1 and clinically used prostaglandins},

author = {Beatriz Díez-Dacal and Francisco J Sánchez-Gómez and Pedro A Sánchez-Murcia and Ivana Milackova and Tahl Zimmerman and Jana Ballekova and Elena García-Martín and José A G Agúndez and Severine Gharbi and Federico Gago and Others},

year  = {2016},

date = {2016-01-01},

journal = {Molecular Pharmacology},

volume = {89},

number = {1},

pages = {42–52},

publisher = {American Society for Pharmacology and Experimental Therapeutics},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Murcia2015,

title = {Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase},

author = {Pedro A Sánchez-Murcia and Marta Ruiz-Santaquiteria and Miguel A Toro and Hector Lucio and María Ángeles Jiménez and Federico Gago and Antonio Jiménez-Ruiz and María-José Camarasa and Sonsoles Velazquez},

year  = {2015},

date = {2015-01-01},

journal = {RSC Advances},

volume = {5},

number = {69},

pages = {55784–55794},

publisher = {Royal Society of Chemistry},

keywords = {},

pubstate = {published},

tppubtype = {article}

}