Biologie structurale intégrative

Enzymes: catalyse, inhibition et méthodologie en cristallographie

Our team aims to study in fine detail the structural basis of ligand binding to  macromolecules involved in important diseases (targets) and the corresponding structure activity relationships (SAR), in order to gather  information for the “hit to lead” discovery process. We determine the crystallographic structures of proteins and macromolecular complexes, in the presence and in the absence of natural or synthetic ligands. We develop new methodologies, in particular for high resolution X-Ray and neutron diffraction, to improve the quality of the structures of ligand-target complexes. We collaborate with several national and international groups for the production of ligands and for the modeling of ligand binding, which we use to complement the experimental structural information.  In summary we apply an integrated approach to Experimental Structure Based Drug Design.
In structural biology our expertise covers cloning, protein expression in prokaryotic and eukaryotic cells, large scale protein production, purification, protein crystallization and protein crystallography. The latter is the main tool to visualize macromolecular complexes.
We develop special crystallographic  methods based both on high resolution X-Rays (PX) and on Neutrons (NPX) diffraction, leading to very accurate models including the  observation of protonation states and hydration. This exceptional level of joint information is then used to explain very precisely the mechanisms of action and inhibition. We also study in detail the thermodynamics of binding. In this sense we apply several biochemical and biophysical techniques, including Isothermal Titration Calorimetry (ITC), Mass Spectrometry (MS), Surface Plasmon Resonance (SPR) and analytical ultra-centrifugation.
As a significant example, we have studied one protein, human Aldose Reductase, at the highest resolution ever obtained so far with X-Ray Crystallography (0.66 Å) for a medium size enzyme (36 kDa). We have used this information for the development of pharmaceutical leads. One of these leads (Fidarestat) is currently in phase III of clinical trials. 

Imprimer Envoyer

Université de Strasbourg

IGBMC - CNRS UMR 7104 - Inserm U 964
1 rue Laurent Fries / BP 10142 / 67404 Illkirch CEDEX / France Tél +33 (0)3 88 65 32 00 / Fax +33 (0)3 88 65 32 01 / directeur.igbmc@igbmc.fr