Structure determination of the inactive conformation of the vasopressin V2 receptor

The conformational flexibility of G protein-coupled receptors (GPCRs) is a prerequisite to sense a variety of stimuli and link them to different signaling partners. Such high plasticity to interact with an important range of signaling partners, representing a challenge for structure determination. Our research interest is to understand the structural basis of the vasopressin V2 receptor (V2R) signal transduction and their allosteric modulation. Our group already solved the V2R active structures in complex with either G proteins or arrestin. We are now working on solving the inactive state of the V2R in complex with an antagonist, the mambaquaretin-1. The last is a toxin that fully inactivate the V2R signaling. By comparing the active and inactive structures at high-resolution, we will decipher the different conformational changes leading to various signal transduction. The goal is to rationally design, on a structural basis, new selective ligands with potential therapeutic value.