A Three‐Site Mechanism for Agonist/Antagonist Selective Binding to Vasopressin Receptors. Issue 28 (17th May 2016)

• Record Type: Journal Article
• Authors: Saleh, Noureldin; Saladino, Giorgio; Gervasio, Francesco L.; Haensele, Elke; Banting, Lee; Whitley, David C.; Sopkova‐de Oliveira Santos, Jana; Bureau, Ronan; Clark, Timothy
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 28(2016)
• Page Start: 8008
• Page End: 8012
• Publication Date: 2016-05-17
• Subjects: G-protein coupled receptors -- hormones -- metadynamics -- molecular dynamics -- receptors; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201602729
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Molecular‐dynamics simulations with metadynamics enhanced sampling reveal three distinct binding sites for arginine vasopressin (AVP) within its V2 ‐receptor (V2 R). Two of these, the vestibule and intermediate sites, block (antagonize) the receptor, and the third is the orthosteric activation (agonist) site. The contacts found for the orthosteric site satisfy all the requirements deduced from mutagenesis experiments. Metadynamics simulations for V2 R and its V1a R‐analog give an excellent correlation with experimental binding free energies by assuming that the most stable binding site in the simulations corresponds to the experimental binding free energy in each case. The resulting three‐site mechanism separates agonists from antagonists and explains subtype selectivity. Abstract : Three distinct binding sites are revealed by molecular‐dynamics simulations with metadynamics enhanced sampling for arginine vasopressin (AVP) within its V2 receptor (V2 R). Two of these, the vestibule (magenta) and intermediate (green) sites, block (antagonize) the receptor, and the third is the orthosteric activation (agonist) site (blue). The resulting three‐site mechanism separates agonists from antagonists and explains subtype selectivity.