Institut Pasteur (IP)

Structural Bioinformatics Unit, Dynamics & drug design group (project leader: Arnaud Blondel)

The Structural Bioinformatics Unit (Head of Unit: Michael Nilges) has a long-standing commitment in bioinformatics developments applied to structure determination, characterization of protein dynamics and mechanistic analysis. In this context, the Dynamics & Drug Design group (group leader: Arnaud Blondel) has developed original methods to model the dynamic and functional motions of proteins to better elaborate effector search strategies. The successful candidate is highly motivated and displays interest in molecular recognition, computational drug design, in the context of finding therapies against infectious diseases. He is expected to have background in computing on unix / linux platforms, and have computational skills such as molecular dynamics, molecular modeling, structure determination, chemoinformatics.

Chemistry and Biocatalysis Unit, Biochemistry and screening group (project leader: Hélène Munier-Lehmann)

The Chemistry and Biocatalysis Unit gathers chemists and biochemists. Research in the Unit focuses on the design and synthesis of new chemical entities (mainly nucleos(t)ide analogues and related heterocyclic compounds) targeting enzymes from nucleoside metabolism, and the characterization of unexplored protein targets. The Biochemistry and screening  group is interested in the structure-function relationships of proteins through multidisciplinary approaches. Our studies have been concentrated on nucleoside monophosphate kinases (NMPKs) and more recently IMP dehydrogenase (IMPDH). Related to the validation of these proteins targets for the development of new anti-infectious agents, we use screening of chemical compounds. The screening activity is devoted to investigating the effect of small molecules mainly in the field of anti-infectious agents, in our research programs or through collaborative projects. The successful candidate will be involved in the characterization of the UMPK from M. tuberculosis, which is a particularly interesting target as no counterpart exists in eukaryotes. With an in-house screening campaign, an allosteric inhibitor with an IC50 of 1 μM that binds to the negative effector binding site has already been identified. The aim of the project will be to better understand the cross-talk between the regulatory (i.e. effector binding sites) and the catalytic (i.e. substrate binding sites) domains. In particular, no structure in the presence of the negative effector (UTP) has been solved so far for any bacterial UMPK, and it is still a matter of intense effort. Work of the student will involve crystallisation trials and the development of an assay to identify novel allosteric inhibitors by screening large chemical libraries. The project lies at the interface between biochemistry, structural biology and chemistry and requires a student with multidisciplinary skills.