Structural basis of tolvaptan binding to the vasopressin V₂ receptor.

ABSTRACT: The vasopressin V₂ receptor (V₂R) is a validated therapeutic target for autosomal dominant polycystic kidney disease (ADPKD), with tolvaptan being the first FDA-approved antagonist. Herein, we used Gaussian accelerated molecular dynamics simulations to investigate the spontaneous binding of tolvaptan to both active and inactive V₂R conformations at the atomic-level. Overall, the binding process consists of two stages. Tolvaptan binds initially to extracellular loops 2 and 3 (ECL2/3) before overcoming an energy barrier to enter the pocket. Our simulations result highlighted key residues (e.g., R181, Y205, F287, F178) involved in this process, which were experimentally confirmed by site-directed mutagenesis. This work provides structural insights into tolvapt

SUBMITTER: Liu HL 

PROVIDER: S-EPMC11489814 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature