|Structural Biochemistry - CNRS URA 2185|
|HEAD||Prof. ALZARI Pedro / firstname.lastname@example.org|
|MEMBERS||Dr ANDRE-LEROUX Gwénaëlle / ARBOGAST Laurence / BARILONE Nathalie / Dr BELLINZONI Marco
Dr BETTON Jean-Michel / FRAYSSE Jocelyne / Dr GIGANTI David / GUILLOU Sandrine / Dr JANIN Yves / Dr PASTORIZA Manuela
SASSOON-CLAVIER Nathalie / Dr SCHAEFFER Francis / SUBRINI Orso / TELLO-MANIGNE Diana / WAGNER Tristan / WLODARCZYK Nicolas
Our research activities are oriented towards the biochemical, biophysical and structural studies of proteins involved in microbial physiology and pathogenesis. Some ongoing projects are described below; additional information can be found in our Web page: http://www.pasteur.fr/recherche/unites/Bstruct.
Ser/Thr phosphorylation in mycobacteria (M. Bellinzoni, P.M. Alzari) Although bacterial signaling mechanisms involve primarily the action of two-component systems, several genes in bacterial genomes code for eukaryotic-like Ser/Thr protein kinases and phosphatases. Our research is focused on (1) investigating the mode of action of these enzymes in Mycobacterium tuberculosis, and (2) elucidating phosphodependent signaling pathways that control central metabolism and cell division in mycobacteria, with the specific goal of identifying new drug targets for potential therapeutic applications.
Regulation of lipid biosynthesis in bacteria (F. Schaeffer, P.M. Alzari) We have previously showed that malonyl-CoA is the specific effector of FapR, a global regulator of fatty acid synthesis in various Gram+ bacteria, and we are carrying out structural and thermodynamic studies of FapR-effector-operator complexes. The mode of action involves an effector-induced disorder-to-order transition in FapR that dissociates the protein from its DNA operator. Structure-based mutants that impair effector binding were shown to abolish regulation in vivo and result in a lethal (super-repressor) phenotype. Our current studies are focused on human pathogens such as S. aureus and L. monocytogenes, to understand their mode of action and validate this homeostatic pathway as a potential therapeutic target.
Protein folding and secretion mechanisms in bacteria (J.M. Betton) Our group studies bacterial quality control systems for the development of more efficient protein expression processes. If they escape the cellular quality-control systems, proteins may aggregate when E. coli cells are exposed to environmental stress or overexpress recombinant genes (protein factories). Current projects include the study of the CpxA/R signal transduction system, which senses perturbations in the periplasm and responds by up-regulating several protein folding and degrading activities.
Medicinal chemistry (Y. Janin) Starting from small molecules of interest in infectious diseases (i.e. tuberculosis, malaria), we work on the improvement of their properties using medicinal chemistry. The goals of our research are to synthesize compounds with potential therapeutic applications and to provide new chemical tools helpful for the unraveling of specific biochemical processes.
Keywords: Mycobacterium tuberculosis, bacterial signaling, protein kinases and phosphatases, two-component systems, regulation of lipid biosynthesis, drug design, bacterial protein expression, X-ray crystallography, microcalorimetry, structural biology
Schujman GE, Guerin M, Buschiazzo A, Schaeffer F, Llarrull LI, Vila AJ, Alzari PM, de Mendoza D. (2006) Structural basis of lipid biosynthesis regulation in Gram-positive bacteria. EMBO J. 25:4074-4083.
Bellinzoni M, Wehenkel A, Shepard W, Alzari PM. (2007) Insights into the catalytic mechanism of PPM Ser/Thr phosphatases from the atomic resolution structures of a mycobacterial enzyme. Structure 15:863-872.
O'Hare H, Duran R, Cervenansky C, Bellinzoni M, Wehenkel A, Pritsch O, Obal G, Baumgartner J, Vialaret J, Johnsson K, Alzari PM. (2008) Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol. Microbiol. 70:1408-1423.
Hindie V, Stroba A, Zhang H, Lopez-Garcia LA, Idrissova L, Zeuzem S, Hirschberg D, Schaeffer F, Jorgensen JD, Engel M, Alzari PM, Biondi RM. (2009) Structure and allosteric effects of low molecular-weight activators on the protein kinase PDK1. Nature Chem. Biol. 5:758-764.
Albanesi D, Martin M, Trajtenberg F, Mansilla MC, Haouz A, Alzari PM, de Mendoza D, Buschiazzo A. (2009) Structural plasticity and catalysis regulation of a thermosensor histidine kinase. Proc. Natl. Acad. Sci. USA 106:16185-16190.
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Activity Reports 2009 - Institut Pasteur
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