{Reference Type}: Journal Article
{Title}: Structural basis of tolvaptan binding to the vasopressin V2 receptor.
{Author}: Liu HL;Zhong HY;Zhang YX;Xue HR;Zhang ZS;Fu KQ;Cao XD;Xiong XC;Guo D;
{Journal}: Acta Pharmacol Sin
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 20
{Factor}: 7.169
{DOI}: 10.1038/s41401-024-01325-5
{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 tolvaptan-V2R interactions, potentially aiding the design of novel antagonists for V2R and other G protein-coupled receptors.