Cryo-EM structure of the V2R:AVP:Gs complex


The cryo-EM structure of the antidiuretic hormone arginine-vasopressin V2 receptor signaling complex


Arginine-vasopressin (AVP) is known as the antidiuretic hormone, and it regulates a vital function of our body, water homeostasis. It plays a role in the kidney at the basolateral membranes of the principal cells of the distal collecting duct of the nephron where it directly interacts with the V2 receptor subtype (V2R), which is a typical G protein-coupled receptor (RCPGs). Upon interaction, AVP activates a signaling pathway leading to fusion of aquaporine water channels to the apical membrane of the cells and consequently to water reabsorption from urine to blood. Coupling of the V2R to the Gs protein constitutes a first key step of the cellular response.

The Team « Multi-scale structural biology » in collaboration with the Team of Bernard Mouillac and Sébastien Granier from the IGF (Montpellier), determined the structure of the AVP-V2R-Gs ternary complex by cryo-electron microscopy single particle analysis in combining the cryo-EM density map with experimental NMR (Nuclear Magnetic Resonance) data obtained by Hélène Déméné (Team « Integrative Biophysics of Membranes », CBS) and computational molecular dynamic simulations developed by Nicolas Floquet at the Institut des Biomolécules Max Mousseron (IBMM).

This study reveals the extremely strong dynamics of the AVP-V2R-Gs ternary complex since three conformational states were observed reflecting different modes of interaction of AVP and the Gs protein. These structures make it possible to understand how certain mutations induce two genetics, congenital nephrogenic diabetes insipidus and the nephrogenic syndrome of inappropriate antidiuresis.

This study paves the way to the development of new therapeutic molecules able to activate or to inhibit its function. This research perspective is crucial regarding patients who are suffering for these pathologies which are difficult to manage.

Link to the article :

Cryo-electron microscopy structure of the antidiuretic hormone arginine-vasopressin V2 receptor signaling complex.
J. Bous, H. Orcel, N. Floquet, C. Leyrat, J. Lai-Kee-Him, G. Gaibelet, A. Ancelin, J. Saint-Paul, S. Trapani, M. Louet, R. Sounier, H. Déméné, S. Granier*, P. Bron*, B. Mouillac*. Science Advances, 7, eabg5628 (2021).