Structural basis of tolvaptan binding to the vasopressin V_(2)receptor  

作　　者：Hong-li Liu Hai-yang Zhong Yi-xiao Zhang Hua-rui Xue Zheng-shuo Zhang Ke-quan Fu Xu-dong Cao Xiao-chun Xiong Dong Guo 

机构地区：[1]Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy,Xuzhou Medical University,Xuzhou,221004,China

出　　处：《Acta Pharmacologica Sinica》2024年第11期2441-2449,共9页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(22377103,22107090 and 22077110);the Natural Science Foundation of Jiangsu Province(BK20200106);the Major Basic Research Project of the Natural Science Research Foundation of the Jiangsu Higher Education Institutions(20KJA350001);the Natural Science Research Project of Jiangsu Universities(21KJB350009);the Scientific Research Foundation for Talented Scholars in Xuzhou Medical University(D2020036,D2022002).

摘　　要：The vasopressin V_(2)receptor(V_(2)R)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 V_(2)R 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-V_(2)R interactions,potentially aiding the design of novel antagonists for V_(2)R and other G protein-coupled receptors.

关 键 词：vasopressin V_(2)receptor(V_(2)R) TOLVAPTAN binding pathway gaussian accelerated molecular dynamics(GaMD)simulations 

分 类 号：R97[医药卫生—药品]