PhD PROPOSAL FOR THE PASTEUR-PARIS UNIVERSITY INTERNATIONAL PROGRAM

 

Deadline for full application: December 15th, 2013

Interviews: March, 2014

Start of the Ph.D.: October 1st, 2014

 

 

Department: Structural Biology and Chemistry

Title of the PhD project: Mechanism of regulation of bacterial nucleotide metabolism enzymes

Name of the lab: Chemistry and Biocatalysis

Head of the lab: Sylvie Pochet

PhD advisor: Hélène Munier-Lehmann

Email address: helene.munier-lehmann@pasteur.fr

Web site address of the lab: http://www.pasteur.fr/ip/easysite/pasteur/en/research/scientific-departm...

Doctoral school affiliation and University: Ecole Doctorale 436 « Médicament, Toxicologie, Chimie, Environnement »; Paris Descartes and Paris Diderot Universities.

 

Presentation of the laboratory and its research topics:

The research projects of the Unit lie at the interface of chemistry and biology, and are mainly focused on the design and synthesis of molecules that interfere with nucleoside metabolism enzymes, and the characterization of unexplored proteins related to this metabolism. The ongoing research aims to a better understanding of cellular processes as invasive bacteria transits through the various stages of their developmental program focusing on those that are the most promising targets for drug development.

 

Description of the project:

The aim of this project is to better understand the role of accessory domains, namely cystathionine-ß-synthase (CBS) domains, in the function and the regulatory mechanism of an essential enzyme (inosine-5’-monophosphate dehydrogenase [1] (IMPDH)) involved in nucleotide metabolism. We will build on the strategy that we successfully established for the Pseudomonas aeruginosa IMPDH [2], which relies on a multi-approach characterization of the whole protein by biochemical and structural biology methods ranging from the molecular-scale (AUC, SAXS) to the atomic-scale (X-ray crystallography), which will be further complemented by other hydrodynamic approaches and native mass spectrometry. Our recent studies [2] shed light on the functional and structural role of the CBS domains in IMPDH regulation and have resulted in the proposal of a new paradigm for IMPDH mechanism of action. Indeed, our results demonstrate: i) an allosteric regulation of IMPDH from P. aeruginosa by Mg-ATP, ii) an octameric macromolecular organization of IMPDHs, distinct from the tetrameric architecture that had been assumed to date and iii) a novel functional role of the CBS modules. Unexplored IMPDHs from different humans-invasive bacteria will be characterized: some of them have been shown to be essential for the pathogen survival suggesting that they constitute attractive targets surprisingly neglected up to now. A better understanding of the role of the CBS modules into the IMPDH regulation will help in the identification of efficient and specific inhibitors targeting the allosteric binding sites that would guide the development of novel antibacterial agents.

 

References:

1. Hedstrom L (2009) IMP dehydrogenase: structure, mechanism, and inhibition. Chem Rev 109: 2903-2928.

2. Labesse G, Alexandre T, Vaupre L, Salard-Arnaud I, Him JL, Raynal B, Bron P, Munier-Lehmann H (2013) MgATP Regulates Allostery and Fiber Formation in IMPDHs. Structure 21: 975-985.

 

Keywords:

Invasive bacteria, nucleotide metabolism, IMPDH, supramolecular assembly, CBS domains, effector binding site, enzymology, structural biology

 

Contact: Hélène Munier-Lehmann, Phone: 33/1 45 68 83 81

Mis à jour le 16/09/2013