徐州医科大学郭栋等研究人员合作揭示托伐普坦与血管加压素V₂受体结合的结构基础。该研究于2024年6月20日在线发表于国际一流学术期刊《中国药理学报》。

据悉，V₂R是常染色体显性多囊肾病（ADPKD）的有效治疗靶点，而托伐普坦是首个获得美国食品与药物管理局批准的拮抗剂。

附：英文原文

Title: Structural basis of tolvaptan binding to the vasopressin V2 receptor

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

Issue&Volume: 2024-06-20

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.

DOI: 10.1038/s41401-024-01325-5

Source: https://www.nature.com/articles/s41401-024-01325-5