|Structural Biochemistry - CNRS URA 2185|
|HEAD||Prof. ALZARI Pedro / email@example.com|
|MEMBERS||Dr ANDRE-LEROUX Gwénaëlle / ARBOGAST Laurence / BARILONE Nathalie / Dr BELLINZONI Marco / Dr BETTON Jean-Michel / FRAYSSE Jocelyne / GUILLOU Sandrine / Dr HINDIE Valérie / Dr JANIN Yves / Dr MANINA Giulia / SASSOON-CLAVIER Nathalie / Dr SCHAEFFER Francis / SUBRINI Orso / TELLO Diana / WAGNER Tristan / Dr. WEHENKEL Anne-Marie
Our research activities are oriented towards the biochemical, biophysical and structural studies of proteins involved in microbial 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, G. Andre-Leroux, P.M. Alzari) Although bacterial signaling mechanisms involve primarily the action of two-component systems, the genome of M. tuberculosis revealed the presence of several genes coding for eukaryotic-like Ser/Thr protein kinases and phosphatases. During the last few years, we have carried out the structural analysis of several of these enzymes to unravel their biochemical modes of action. We showed that some of these proteins (such as kinase PknB) are essential for TB growth and represent promising targets for drug design. Our efforts are now focused on elucidating the kinase-mediated signalling pathway(s) in TB and developing specific inhibitors with 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-DNA complexes from different bacteria (B. subtilis, S. aureus, L. monocytogenes). 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 in B. subtilis. 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). The CpxA/R signal transduction system senses perturbations in the periplasm and responds by up-regulating several protein folding and degrading activities. For these studies we use cell-free expression systems to express membrane proteins in the presence of detergent micelles. Current projects include the function of the periplasmic protease DegP/HtrA, and biochemical and structural analysis of proteins involved in the CpxA/R system.
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, regulation of lipid biosynthesis, drug design, bacterial protein expression, X-ray crystallography, microcalorimetry, structural biology
1. Buschiazzo A, Goytia M, Schaeffer F, Degrave W, Shepard W, Gregoire C, Chamond N, Cosson A, Berneman A, Coatnoan N, Alzari PM, Minoprio P. (2006) Crystal structure, catalytic mechanism and mitogenic properties of Trypanosoma cruzi proline racemase. Proc. Natl. Acad. Sci. USA 103:1705-1710.
2. 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.
3. 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.
4. Mouratou B, Schaeffer F, Guilvout I, Tello-Manigne D, Pugsley AP, Alzari PM, Pecorari F. (2007) Remodeling a DNA binding protein as a specific in vivo inhibitor of bacterial secretin PulD. Proc. Natl. Acad. Sci. USA 104:17983-17988.
5. 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.
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Activity Reports 2009 - Institut Pasteur
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