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A Three‐Site Mechanism for Agonist/Antagonist Selective Binding to Vasopressin Receptors
Author(s) -
Saleh Noureldin,
Saladino Giorgio,
Gervasio Francesco L.,
Haensele Elke,
Banting Lee,
Whitley David C.,
Sopkovade Oliveira Santos Jana,
Bureau Ronan,
Clark Timothy
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201602729
Subject(s) - metadynamics , agonist , binding site , vasopressin , chemistry , vasopressin receptor , receptor , biophysics , stereochemistry , antagonist , molecular dynamics , biochemistry , biology , computational chemistry , endocrinology
Molecular‐dynamics simulations with metadynamics enhanced sampling reveal three distinct binding sites for arginine vasopressin (AVP) within its V 2 ‐receptor (V 2 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 V 2 R and its V 1a 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.