A5056845230- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Biochemical and Molecular Research
- Enzyme Structure and Function
- Receptor Mechanisms and Signaling
- Nicotinic Acetylcholine Receptors Study
- Carbohydrate Chemistry and Synthesis
- Glycosylation and Glycoproteins Research
- Cancer therapeutics and mechanisms
- Monoclonal and Polyclonal Antibodies Research
- RNA and protein synthesis mechanisms
- Fluorine in Organic Chemistry
- Chemical Reactions and Isotopes
- Microbial Metabolic Engineering and Bioproduction
- Porphyrin Metabolism and Disorders
- Enzyme Production and Characterization
- Amino Acid Enzymes and Metabolism
- Bacterial Genetics and Biotechnology
- Neuroscience and Neuropharmacology Research
- Antifungal resistance and susceptibility
- Diagnosis and treatment of tuberculosis
- Photoreceptor and optogenetics research
- Antimicrobial Peptides and Activities
- Metabolism and Genetic Disorders
- Computational Drug Discovery Methods
Institut Pasteur
2012-2024
Université Paris Cité
2015-2023
Centre National de la Recherche Scientifique
2012-2023
Institut Pprime
2021
Signalisation Fonctionnelle des Canaux Ioniques et Récepteurs
2020
Délégation Paris 7
2015-2019
Sorbonne Paris Cité
2015-2017
Centre de Biologie Structurale
2016
Two-component regulatory signal transduction systems are important elements of the adaptative response prokaryotes to a variety environmental stimuli. Disruption PhoP-PhoR in Mycobacterium tuberculosis dramatically attenuates virulence, implying that this system directly and/or indirectly coordinates expression virulence factors whose identity remains be established. Interestingly, knockingout two-component M. Mt103, dramatic changes colonial morphology, cording properties, and reactivity...
The receptor-like protein kinase PknB from Mycobacterium tuberculosis is encoded by the distal gene in a highly conserved operon, present all actinobacteria, that may control cell shape and division. Genes coding for PknB-like are also found many more distantly related gram-positive bacteria. Here, we report pknB can be disrupted allelic replacement M. saprophyte smegmatis only presence of second functional copy gene. We demonstrate eukaryotic Ser/Thr inhibitors, which inactivate vitro with...
Summary Mycobacterium tuberculosis and other pathogenic mycobacterial species produce large amounts of a glycogen‐like α‐glucan that represents the major polysaccharide their outermost capsular layer. To determine role surface‐exposed glucan in physiology virulence these bacteria, orthologues glg genes involved biosynthesis glycogen Escherichia coli were identified M. H37Rv inactivated by allelic replacement. Biochemical analyses mutants complemented strains indicated synthesis involves...
Mycobacterium tuberculosis PknB is an essential receptor‐like protein kinase involved in cell growth control. Here, we demonstrate that mitoxantrone, anthraquinone derivative used cancer therapy, a inhibitor capable of preventing mycobacterial growth. The structure the complex reveals mitoxantrone partially occupies adenine‐binding pocket PknB, providing framework for design compounds with potential therapeutic applications. crystallizes as ‘back‐to‐back’ homodimer identical to those...
To combat the emergence of drug-resistant strains Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening a library 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, intracellular states: 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both harbored mutations ethA...
Similarities between Mycobacterium tuberculosis phoP-phoR mutants and the attenuated laboratory strain M. H37Ra in terms of morphological cytochemical properties, lipid content, gene expression virulence attenuation prompted us to analyze functionality this two-component regulator latter strain. Sequence analysis revealed a base substitution resulting one-amino-acid change likely DNA-binding region PhoP relative H37Rv. Using gel-shift assays, we show that mutation abrogates ability protein...
Alpha-ketoglutarate is a key metabolic intermediate at the crossroads of carbon and nitrogen metabolism, whose fate tightly regulated. In mycobacteria protein GarA regulates tricarboxylic acid cycle glutamate synthesis by direct binding regulation three enzymes that use α-ketoglutarate. GarA, in turn, thought to be regulated via phosphorylation kinase G other kinases. We have investigated requirement for during growth vitro macrophages. was found essential Mycobacterium tuberculosis, but...
Glycosylated p-hydroxybenzoic acid methyl esters and structurally related phenolphthiocerol glycolipids are important virulence factors of Mycobacterium tuberculosis. Although both types molecules thought to be derived from acid, the origin this putative biosynthetic precursor in mycobacteria remained established. We describe characterization a transposon mutant M. tuberculosis deficient production all forms derivatives. The was found inserted Rv2949c, gene located vicinity polyketide...
Arabinogalactan (AG) and lipoarabinomannan (LAM) are the two major cell wall (lipo)polysaccharides of mycobacteria. They share arabinan chains made linear segments alpha-1,5-linked D-Araf residues with some alpha-1,3-branching, biosynthesis which offers opportunities for new chemotherapeutics. In search missing arabinofuranosyltransferases (AraTs) responsible formation domains AG LAM in Mycobacterium tuberculosis, we identified Rv0236c (AftD) as a putative membrane-associated...
Abstract GABA A receptors mediate most inhibitory synaptic transmission in the brain of vertebrates. Following binding and fast activation, these undergo a slower desensitization, conformational pathway which remains largely elusive. To explore mechanism we used concatemeric α1β2γ2 to selectively introduce gain-of-desensitization mutations one subunit at time. library twenty-six mutant combinations was generated their bi-exponential macroscopic desensitization rates measured. Introducing...
Mycobacteria produce two unusual polymethylated polysaccharides, the 6-O-methylglucosyl-containing lipopolysaccharides (MGLP) and 3-O-methylmannose which have been shown to regulate fatty acid biosynthesis in vitro. A cluster of genes dedicated synthesis MGLP was identified Mycobacterium tuberculosis smegmatis. Overexpression putative glycosyltransferase gene Rv3032 M. smegmatis greatly stimulated production, whereas targeted disruption that methyltransferase MSMEG2349 resulted a dramatic...
The arabinogalactan (AG) of slow growing pathogenic Mycobacterium spp. is characterized by the presence galactosamine (GalN) modifying some interior branched arabinosyl residues. biosynthetic origin this substituent and its role(s) in physiology and/or pathogenicity mycobacteria are not known. We report on discovery a polyprenyl-phospho-N-acetylgalactosaminyl synthase (PpgS) glycosyltransferase Rv3779 from tuberculosis required, respectively, for providing transferring GalN substrate...
Abstract The human α7 nicotinic receptor is a pentameric channel mediating cellular and neuronal communication. It has attracted considerable interest in designing ligands for the treatment of neurological psychiatric disorders. To develop novel class ligands, we recently generated two nanobodies named E3 C4, acting as positive allosteric modulator silent ligand, respectively. Here, solved cryo-electron microscopy structures nanobody-receptor complexes. C4 bind to common epitope involving...
α-Ketoacid dehydrogenases are large multi-enzyme machineries that orchestrate the oxidative decarboxylation of α-ketoacids with concomitant production acyl-CoA and NADH. The first reaction, catalysed by α-ketoacid decarboxylases (E1 enzymes), needs a thiamine diphosphate cofactor represents overall rate-limiting step. Although catalytic cycles E1 from pyruvate dehydrogenase (E1p) branched-chain (E1b) complexes have been elucidated, little structural information is available on E1o, component...
Forkhead-associated (FHA) domains are modules that bind to phosphothreonine (pThr) residues in signaling cascades. The FHA-containing mycobacterial protein GarA is a central element of phosphorylation-dependent pathway redirects metabolic flux response amino acid starvation or cell growth requirements. acts as ON/OFF molecular switch. In its nonphosphorylated ON state, the FHA domain engages phosphorylation-independent interactions with various enzymes orchestrate nitrogen flow, such...
ABSTRACT Isoxyl (ISO), a thiourea derivative that was successfully used for the clinical treatment of tuberculosis during 1960s, is an inhibitor synthesis oleic and mycolic acids in Mycobacterium . Its effect on acid has been shown to be attributable its inhibitory activity stearoyl-coenzyme A desaturase DesA3, but enzymatic target(s) pathway remains identified. With goal elucidating mode action ISO, we have isolated number spontaneous ISO-resistant mutants M. undertaken their genotypic...
We report the synthesis and biochemical evaluation of selective inhibitors class II (zinc-dependent) fructose bisphosphate aldolases. The most active compound is a simplified analogue bisphosphate, bearing well-positioned metal chelating group. It powerful highly competitive inhibitor isolated crystallographic studies this bound in site Helicobacter pylori enzyme. also shows activity against Mycobacterium tuberculosis isolates.
Rv1098c and bind by X‐ray crystallography ( View interaction )
The α7 nicotinic acetylcholine receptor (nAChR), a potential drug target for treating cognitive disorders, mediates communication between neuronal and non-neuronal cells. Although many competitive antagonists, agonists, partial-agonists have been found synthesized, they not led to effective therapeutic treatments. In this context, small molecules acting as positive allosteric modulators binding outside the orthosteric, acetylcholine, site attracted considerable interest. Two single-domain...
Signal transduction mediated by Ser/Thr phosphorylation in Mycobacterium tuberculosis has been intensively studied the last years, as its genome harbors eleven genes coding for eukaryotic-like kinases. Here we describe crystal structure and autophosphorylation sites of catalytic domain PknA, one two protein kinases essential pathogen's survival. The ligand-free kinase shows an auto-inhibited conformation similar to that observed human Tyr Src-family. These results reinforce high conservation...