Annuaire
2023
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Structural Studies of Pif1 Helicases from Thermophilic Bacteria
- Journal : Microorganisms
- 2023
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Nucleosome dyad determines the H1 C-terminus collapse on distinct DNA arms
- Journal : Structure
- 2023
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Nonstructural N- and C-tails of Dbp2 confer the protein full helicase activities
- Journal : J Biol Chem
- 2023
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One model fits all: Combining inference and simulation of gene regulatory networks
- Journal : PLoS Comput Biol
- 2023
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Functional analysis of Wolbachia Cid effectors unravels cooperative interactions to target host chromatin during replication
- Journal : PLOS Pathogens
- 2023
- Wolbachia are common bacteria among terrestrial arthropods. These endosymbionts transmitted through the female germline manipulate their host reproduction through several mechanisms whose most prevalent form called Cytoplasmic Incompatibility -CI- is a conditional sterility syndrome eventually favoring the infected progeny. Upon fertilization, the sperm derived from an infected male is only compatible with an egg harboring a compatible Wolbachia strain, this sperm leading otherwise to embryonic death. The Wolbachia Cif factors CidA and CidB responsible for CI and its neutralization function as a Toxin-Antitoxin system in the mosquito host Culex pipiens . However, the mechanism of CidB toxicity and its neutralization by the CidA antitoxin remain unexplored. Using transfected insect cell lines to perform a structure-function analysis of these effectors, we show that both CidA and CidB are chromatin interactors and CidA anchors CidB to the chromatin in a cell-cycle dependent-manner. In absence of CidA, the CidB toxin localizes to its own chromatin microenvironment and acts by preventing S-phase completion, independently of its deubiquitylase -DUB- domain. Experiments with transgenic Drosophila show that CidB DUB domain is required together with CidA during spermatogenesis to stabilize the CidA-CidB complex. Our study defines CidB functional regions and paves the way to elucidate the mechanism of its toxicity.
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Facilitating CG Simulations with MAD: The MArtini Database Server
- Journal : Journal of Chemical Information and Modeling
- 2023
- The MArtini Database (MAD - https://mad.ibcp.fr) is a web server designed for the sharing of structures and topologies of molecules parametrized with the Martini coarse-grained (CG) force field. MAD can also convert atomistic structures into CG structures and prepare complex systems (including proteins, lipids, etc.) for molecular dynamics (MD) simulations at the CG level. It is dedicated to the generation of input files for Martini 3, the most recent version of this popular CG force field. Specifically, the MAD server currently includes tools to submit or retrieve CG models of a wide range of molecules (lipids, carbohydrates, nanoparticles, etc.), transform atomistic protein structures into CG structures and topologies, with fine control on the process and assemble biomolecules into large systems, and deliver all files necessary to start simulations in the GROMACS MD engine.
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Specific Xray diffraction patterns of membrane proteins caused by secondary structure collinearity.
- Journal : Biochim Biophys Acta Biomembr
- 2023
- Diffraction anisotropy is a phenomenon that impacts more specifically membraneproteins, compared to soluble ones, but the reasons for this discrepancy remainedunclear. Often, it is referred to a difference in resolution limits betweenhighest and lowest diffraction limits as a signature for anisotropy. We show inthis article that there is no single correlation between anisotropy anddifference in resolution limits, with notably a substantial number of structuresdisplaying various anisotropy with no difference in resolution limits. We furtherinvestigated diffraction intensity profiles, and observed a peak centred on 4.9 Åresolution more predominant in membrane proteins. Since this peak is in theregion corresponding to secondary structures, we investigated the influence ofsecondary structure ratio. We showed that secondary structure content has littleinfluence on this profile, while secondary structure collinearity in membraneproteins correlate with a stronger peak. Finally, we could further show that thepresence of this peak is linked to higher diffraction anisotropy. These resultsbring to light a specific diffraction of membrane protein crystals, which callsfor a specific handling by crystallographic software. It also brings anexplanation for investigators struggling with their anisotropic data.
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Internal Normal Mode Analysis Applied to RNA Flexibility and Conformational Changes.
- Journal : J Chem Inf Model
- 2023
- We investigated the capability of internal normal modes to reproduce RNAflexibility and predict observed RNA conformational changes and, notably, thoseinduced by the formation of RNA-protein and RNA-ligand complexes. Here, weextended our iNMA approach developed for proteins to study RNA molecules using asimplified representation of the RNA structure and its potential energy. Threedata sets were also created to investigate different aspects. Despite all theapproximations, our study shows that iNMA is a suitable method to take intoaccount RNA flexibility and describe its conformational changes opening the routeto its applicability in any integrative approach where these properties arecrucial.
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Rational Prediction of PROTAC-Compatible Protein-Protein Interfaces by Molecular Docking.
- Journal : J Chem Inf Model
- 2023
- Proteolysis targeting chimeras (PROTACs) are heterobifunctional ligands thatmediate the interaction between a protein target and an E3 ligase, resulting in aternary complex, whose interaction with the ubiquitination machinery leads totarget degradation. This technology is emerging as an exciting new avenue fortherapeutic development, with several PROTACs currently undergoing clinicaltrials targeting cancer. Here, we describe a general and computationallyefficient methodology combining restraint-based docking, energy-based rescoring,and a filter based on the minimal solvent-accessible surface distance to producePROTAC-compatible PPIs suitable for when there is no a priori known PROTACligand. In a benchmark employing a manually curated data set of 13 ternarycomplex crystals, we achieved an accuracy of 92% when starting from boundstructures and 77% when starting from unbound structures, respectively. Ourmethod only requires that the ligand-bound structures of the monomeric forms ofthe E3 ligase and target proteins be given to run, making it general, accurate,and highly efficient, with the ability to impact early-stage PROTAC-based drugdesign campaigns where no structural information about the ternary complexstructure is available.
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Conformational space exploration of cryo-EM structures by variability refinement.
- Journal : Biochim Biophys Acta Biomembr
- 2023
- Cryo-EM observation of biological samples enables visualization of sampleheterogeneity, in the form of discrete states that are separable, or continuousheterogeneity as a result of local protein motion before flash freezing.Variability analysis of this continuous heterogeneity describes the variancebetween a particle stack and a volume, and results in a map series describing thevarious steps undertaken by the sample in the particle stack. While thisobservation is absolutely stunning, it is very hard to pinpoint structuraldetails to elements of the maps. In order to bridge the gap between observationand explanation, we designed a tool that refines an ensemble of structures intoall the maps from variability analysis. Using this bundle of structures, it iseasy to spot variable parts of the structure, as well as the parts that are notmoving. Comparison with molecular dynamics simulations highlights the fact thatthe movements follow the same directions, albeit with different amplitudes.Ligand can also be investigated using this method. Variability refinement isavailable in the Phenix software suite, accessible under the program namephenix.varref.
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Potential binding modes of the gut bacterial metabolite, 5-hydroxyindole, to the intestinal L-type calcium channels and its impact on the microbiota in rats
- Journal : Gut Microbes
- 2023
- Intestinal microbiota and microbiota-derived metabolites play a key role in regulating the host physiology. Recently, we have identified a gut-bacterial metabolite, namely 5-hydroxyindole, as a potent stimulant of intestinal motility via its modulation of L-type voltage-gated calcium channels located on the intestinal smooth muscle cells. Dysregulation of L-type voltage-gated calcium channels is associated with various gastrointestinal motility disorders, including constipation, making L-type voltage-gated calcium channels an important target for drug development. Nonetheless, the majority of currently available drugs are associated with alteration of the gut microbiota. Using 16S rRNA sequencing this study shows that, when administered orally, 5-hydroxyindole has only marginal effects on the rat cecal microbiota. Molecular dynamics simulations propose potential-binding pockets of 5-hydroxyindole in the α1 subunit of the L-type voltage-gated calcium channels and when its stimulatory effect on the rat colonic contractility was compared to 16 different analogues, ex-vivo, 5-hydroxyindole stood as the most potent enhancer of the intestinal contractility. Overall, the present findings imply a potential role of microbiota-derived metabolites as candidate therapeutics for targeted treatment of slow intestinal motility-related disorders including constipation.
Link to PubMed entry