A5009508483- Protein Structure and Dynamics
- Estrogen and related hormone effects
- Alzheimer's disease research and treatments
- Retinoids in leukemia and cellular processes
- Enzyme Structure and Function
- Prion Diseases and Protein Misfolding
- Computational Drug Discovery Methods
- Cervical Cancer and HPV Research
- Vitamin D Research Studies
- Biotin and Related Studies
- Neurological diseases and metabolism
- Proteins in Food Systems
- Cytokine Signaling Pathways and Interactions
- Bacteriophages and microbial interactions
- Supramolecular Self-Assembly in Materials
- Lipid Membrane Structure and Behavior
- Bioinformatics and Genomic Networks
- Chemokine receptors and signaling
- RNA and protein synthesis mechanisms
- DNA and Nucleic Acid Chemistry
- Cancer, Stress, Anesthesia, and Immune Response
- Microbial Natural Products and Biosynthesis
- Protein Kinase Regulation and GTPase Signaling
- Virus-based gene therapy research
- Advanced Fluorescence Microscopy Techniques
Centre National de la Recherche Scientifique
2009-2024
Inserm
2012-2024
Université de Strasbourg
2012-2024
Institut de génétique et de biologie moléculaire et cellulaire
2013-2024
Icahn School of Medicine at Mount Sinai
2020
Canadian Nautical Research Society
2019
Integrated Structural Biology Grenoble
2013-2018
University of Cambridge
2014-2015
Université Paris Cité
2008-2014
Laboratoire de Biochimie Théorique
2009-2014
Significance The assembly of normally soluble proteins into large fibrils, known as amyloid aggregation, is associated with a range pathologies. Prefibrillar protein oligomers but not the grown fibers are believed to be main toxic agents. It unresolved if these necessary for fibril or just dangerous byproduct. We show using computer simulations that, at physiological concentrations, formation must proceed through two-step process including prefibrillar oligomers. find that there an optimal...
Analysis of an intrinsically disordered protein (IDP) reveals underlying multifunnel structure for the energy landscape. We suggest that such 'intrinsically disordered' landscapes, with a number very different competing low-energy structures, are likely to characterise IDPs, and provide useful way address their properties. In particular, IDPs present in many cellular interaction networks, several questions arise regarding how they bind partners. Are conformations resembling bound selected...
Coarse-grained protein models with various levels of granularity and degrees freedom offer the possibility to explore many phenomena including folding, assembly, recognition in terms dynamics thermodynamics that are inaccessible all-atom representations explicit aqueous solution. Here, we present a refined version coarse-grained optimized potential for efficient structure prediction (OPEP) based on six-bead representation. The OPEP 4.0 parameter set, which uses new analytical formulation...
Many proteins display a strand-loop-strand motif in their amyloid fibrillar states. For instance, the β-protein, Aβ1−40, associated with Alzheimer's disease, displays loop at positions 22−28 its fibril state. It has been suggested that this could appear early aggregation process, but quantitative information regarding presence small oligomers remains scant. Because residues 1−15 are disordered Aβ1−42 fibrils and Aβ10−35 forms vitro, we select peptide Aβ16−35, centered on determine structures...
The amyloid-β protein (Aβ) oligomers are believed to be the main culprits in cytoxicity of Alzheimer's disease (AD) and p3 peptides (Aβ17-42 fragments) present AD amyloid plaques. Many small-molecule or peptide-based inhibitors known slow down Aβ aggregation reduce toxicity vitro, but their exact modes action remain determined since there has been no atomic level Aβ(p3)-drug oligomers. In this study, we have structure Aβ17-42 trimers both aqueous solution presence five using a multiscale...
Current approaches aimed at determining the free energy surface of all-atom medium-size proteins in explicit solvent are slow and not sufficient to converge equilibrium properties. To ensure a proper sampling configurational space, it is preferable use reduced representations such as implicit and/or coarse-grained protein models, which much lighter computationally. Each model must be verified, however, that can recover experimental structures thermodynamics. Here we test OPEP with replica...
Coumermycin A1 is a natural aminocoumarin that inhibits bacterial DNA gyrase, member of the GHKL proteins superfamily. We report here first cocrystal structures gyrase B bound to coumermycin A1, revealing one molecule traps simultaneously two ATP-binding sites. The inhibited dimers from different species adopt distinct sequence-dependent conformations, alternative ATP-bound form. These provide basis for rational development derivatives antibiotherapy and biotechnology applications.
Aggregation of the Abeta1-40/Abeta1-42 peptides is a key factor in Alzheimer's disease. Though inhibitory effect N-methylated Abeta16-22 (mAbeta16-22) well characterized vitro, there little information on how they disassemble full-length Abeta fibrils or block fibril formation. Here, we report coarse-grained implicit solvent molecular dynamics (MD) and replica exchange (REMD) simulations mAbeta16-22 monomers, then preformed six-chain bilayer with either four copies mAbeta16-22. Our show that...
Alterations in estrogen-mediated cellular signaling have largely been implicated the pathogenesis of breast cancer. Here, we investigated regulation a splice variant estrogen receptor, namely receptor (ERα-36), associated with poor prognosis cancers. Coupling vitro and vivo approaches determined precise sequential molecular events new network an ERα-negative cell line original patient-derived xenograft. After treatment, ERα-36 rapidly associates Src at level plasma membrane, initiating...
Background PGC-1α is a crucial regulator of cellular metabolism and energy homeostasis that functionally acts together with the estrogen-related receptors (ERRα ERRγ) in regulation mitochondrial metabolic gene networks. Dimerization ERRs pre-requisite for interactions other coactivators, eventually leading to transactivation. It was suggested recently (Devarakonda et al) binds strikingly different manner ERRγ ligand-binding domains (LBDs) compared its mode binding ERRα nuclear (NRs), where...
The E6 oncoproteins of high-risk mucosal (hrm) human papillomaviruses (HPVs) contain a pocket that captures LxxLL motifs and C-terminal motif recruits PDZ domains, with both functions being crucial for HPV-induced oncogenesis. A chimeric protein was built by fusing domain an motif, known to bind E6. NMR spectroscopy, calorimetry mammalian complementation assay converged show the resulting PDZ-LxxLL chimera is bivalent nanomolar ligand E6, while its separated components are only micromolar...
Castration-resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance its first-line treatment, docetaxel. The benefits of vitamin D on (PCa) progression have been previously reported. This study aimed investigate the effects chemoresistance in CRPC.
The conversion of the prion protein (PrP) from its cellular form, PrPC, to pathogenic scrapie PrPSc, is a key event in neurodegenerative transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD). PrPC characterized by three helices (H1-H3) and small antiparallel beta-sheet. One working hypothesis for TSE causation that oligomeric forms PrP are proximate neurotoxic agents. Because these states transient character, current experimental studies have failed provide atomic...
Actual use of the active form vitamin D (calcitriol or 1α,25-dihydroxyvitamin D3) to treat hyperproliferative disorders is hampered by calcemic effects, hence continuous development chemically modified analogues with dissociated profiles. Structurally distinct nonsecosteroidal have been developed mimic calcitriol activity profiles low calcium serum levels. Here, we report crystallographic study nuclear receptor (VDR) ligand binding domain in complexes six harboring two three phenyl rings....
Human prion diseases are a heterogeneous group of fatal neurodegenerative disorders, characterized by the deposition partially protease-resistant protein (PrPres), astrocytosis, neuronal loss and spongiform change in brain. Among inherited forms that represent 15% patients, different phenotypes have been described depending on variations detected at positions within gene. Here, we report new mechanism governing phenotypic variability diseases. First, observed substitution residue 211 with...
Persistent HPV infections can be associated with the development of several cancers. The ability to persist depends on virus escape host immune system.
Nuclear receptor proteins constitute a superfamily of that function as ligand dependent transcription factors. They are implicated in the transcriptional cascades underlying many physiological phenomena, such embryogenesis, cell growth and differentiation, apoptosis, making them one major signal transduction paradigms metazoans. Regulation these receptors occurs through binding hormones, case retinoic acid (RAR), (RA). In addition to this canonical scenario RAR activity, recent discoveries...
Abstract Non-canonical residues, caps, crosslinks, and nicks are important to many functions of DNAs, RNAs, proteins, complexes. However, we do not fully understand how networks such non-canonical macromolecules generate behavior. One barrier is our limited formats for describing macromolecules. To overcome this barrier, develop BpForms BcForms , a toolkit representing the primary structure as combinations nicks. The can help omics researchers perform quality control exchange information...
Characterizing the variability within an ensemble of protein structures is a common requirement in structural biology and bioinformatics. With increasing number becoming available, there need for new tools capable automating comparison large structures. We present Protein Structural Statistics (PSS), command-line program written Perl Unix-like environments, dedicated to calculation statistics set proteins. PSS can perform multiple sequence alignments, structure superpositions, calculate...
Depending on the amino acid sequence, as well local environment, some peptides have capability to fold into multiple secondary structures. Conformational switching between such structures is a key element of protein folding and aggregation. Specifically, understanding molecular mechanism underlying transition from an α-helix β-hairpin critical because it thought be harbinger amyloid assembly. In this study, we explore energy landscape for 18-residue peptide (DP5), designed by Araki Tamura...
Nuclear receptors are ligand-activated transcription factors that modulate gene regulatory networks from embryonic development to adult physiology and thus represent major targets for clinical interventions in many diseases. Most nuclear function either as homodimers or heterodimers. The dimerization is crucial regulation by receptors, extending the repertoire of binding sites promoters enhancers target genes via combinatorial interactions. Here, we focused our attention on an unusual...