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Structural basis of tolvaptan binding to the vasopressin V 2 receptor
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Structural basis of tolvaptan binding to the vasopressin V 2 receptor
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Structural basis of tolvaptan binding to the vasopressin V 2 receptor
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Journal Article
Structural basis of tolvaptan binding to the vasopressin V 2 receptor
2024
Overview
The vasopressin V
receptor (V
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
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
R interactions, potentially aiding the design of novel antagonists for V
R and other G protein-coupled receptors.
