Analyse d'interactions moléculaires par RMN : Étude de la DHFR en présence d'osmolytes et structures de pseudopeptides antimicrobiens en environnement membranaire

Abstract : This manuscript is divided in two chapters; the first one deals with the osmolytes effect on the DHFR enzyme (dihydrofolate reductase) and the second one presents a structural study of antimicrobial pseudopeptides in model membranes. The osmolytes are small molecules accumulated by cells and tissues of a wide variety of organisms in response to hyperosmotic stress, in order to maintain the cellular volume. They contribute to saving the cellular integrity and to stabilizing the macromolecules from various environmental stresses. Nevertheless, enzyme activity is sometimes inhibited by these cosolutes and the molecular basis of their effects on the proteins properties is of great interest. We studied the DHFR, which is a key enzyme in the metabolism, in presence of osmolytes. We demonstrate that its overall structure is maintained, while the osmolytes stabilize the DHFR structure, they inhibit its activity at the same time. The dissociation rate constant, koff, of substrate analogues decreases with increasing the osmolyte concentrations and reflects the variation of DHFR catalytic rate. The study of the DHFR dynamic on several timescales gives answer on the origin of the DHFR inhibition in presence of osmolytes. The second chapter concerns the study of the structure-activity relationship for several antimicrobial peptides. The main objective of this project is to develop new drugs to face the increasing antibiotic resistance of pathogens against conventional antibiotics. We solved NMR solution structure and studied the behavior of peptides and pseudopeptides in various model membranes, SDS micelles and phospholipids, in order to propose a mechanism of action for each of them.
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Contributor : Baptiste Legrand <>
Submitted on : Thursday, February 4, 2010 - 3:23:00 PM
Last modification on : Wednesday, May 16, 2018 - 11:22:32 AM
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  • HAL Id : tel-00453405, version 1

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Baptiste Legrand. Analyse d'interactions moléculaires par RMN : Étude de la DHFR en présence d'osmolytes et structures de pseudopeptides antimicrobiens en environnement membranaire. Biochimie [q-bio.BM]. Université de Rennes I, 2009. Français. ⟨tel-00453405⟩

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