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Structural basis of tolvaptan binding to the vasopressin V2 receptor

   
@article{APS11132,
	author = {Hong-li Liu and Hai-yang Zhong and Yi-xiao Zhang and Hua-rui Xue and Zheng-shuo Zhang and Ke-quan Fu and Xu-dong Cao and Xiao-chun Xiong and Dong Guo},
	title = {Structural basis of tolvaptan binding to the vasopressin V2 receptor},
	journal = {Acta Pharmacologica Sinica},
	volume = {45},
	number = {11},
	year = {2024},
	keywords = {},
	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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/11132}
}