A Three-Site Mechanism for Agonist/Antagonist Selective Binding to Vasopressin Receptors
Molecular‐dynamics simulations with metadynamics enhanced sampling reveal three distinct binding sites for arginine vasopressin (AVP) within its V2‐receptor (V2R). Two of these, the vestibule and intermediate sites, block (antagonize) the receptor, and the third is the orthosteric activation (agonis...
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Published in | Angewandte Chemie (International ed.) Vol. 55; no. 28; pp. 8008 - 8012 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Germany
Blackwell Publishing Ltd
04.07.2016
Wiley Subscription Services, Inc |
Edition | International ed. in English |
Subjects | |
Online Access | Get full text |
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Summary: | Molecular‐dynamics simulations with metadynamics enhanced sampling reveal three distinct binding sites for arginine vasopressin (AVP) within its V2‐receptor (V2R). 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 V2R and its V1aR‐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.
Three distinct binding sites are revealed by molecular‐dynamics simulations with metadynamics enhanced sampling for arginine vasopressin (AVP) within its V2 receptor (V2R). 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. |
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Bibliography: | ark:/67375/WNG-MDFPDMT0-Z Deutsche Forschungsgemeinschaft European Union EPSRC - No. EP/M013898/1 istex:8325FFC367B809F31B31E8B48CB565CCA4C8D943 ArticleID:ANIE201602729 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1433-7851 1521-3773 |
DOI: | 10.1002/anie.201602729 |