Structural and functional characterization of different states of the arginine vasopressin V2 receptor

G protein-coupled receptors (GPCR) are the largest superfamily of cell surface signaling membrane proteins and the targets of 30% of marketed drugs for many human diseases.

They respond to diverse extracellular stimuli by transmitting the signal across the membrane and activating a number of intracellular signaling pathways.

To sense these stimuli and couple to signaling partners such as G proteins, these transmembrane domains have a high conformational flexibility, representing a challenge for structure determination.

Both improvements of GPCR expression and purification, and the cryo-EM revolution have led to structurally characterized GPCR to better understand these signaling key players.

However, defining active states of a given receptor is still a difficult challenge that led to success only for a dozen different GPCR. This project focus on the characterization of different states of the arginine vasopressin (AVP) V2 receptor (V2R). The V2R is considered as a receptor model for small peptides and hormones and is a crucial therapeutic target.

The atomic resolution data will contribute to a better knowledge of the V2R transmembrane signaling.

The comparison of the different active states of the V2R to the inactive state of V2R will provide key information for deciphering the molecular events leading to receptor activation.

Then, blocking the V2R with antagonists is a validated therapeutic avenue for two unmet medical needs, hyponatremia and autosomal dominant polycystic kidney disease.

V2R interacts not only with Gs protein but also with arrestins, the development of biased agonists that selectively activate or inhibit one signaling cascade among all triggered by the natural hormone is also a very promising therapeutic line.

Keeping in mind the interest of antagonists/inverse agonists and biased agonists of the V2R for human health, we expect our data will have a major impact on drug discovery, in addition to be of general interest in terms of scientific impact.