Structural basis of GPCR activation mechanism by using photoswitchable ligand, and time-resolved X-ray diffraction

This project aims at deciphering the structural dynamics of G protein-coupled receptor (GPCRS) seven transmembrane domain (7TM) bound to a photoswitchable ligand and to decipher the structural basis of GPCRs activity. Photopharmacology is a new approach that allows controlling receptor activity by combining light-operated ligands and light stimulation. Photoswitchable ligands offer the possibility to explore the conformational dynamics of GPCRs activation mechanisms. We will combine GPCR photoswitchable ligand and time-resolved X-ray crystallography to decipher light-induced 7TM conformational changes and side-chain motions that define the structural basis of GPCR activity. Finally, GPCRs are validated drug target and their dysfunction is associated to numerous pathologies and neurologic disorders. This project will opens doors to structure-based drug design taking into account the knowledge of mGlu5 7TM structural dynamics.