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Angew Chem Int Ed Engl. 2016 Jul 4;55(28):8008-12. doi: 10.1002/anie.201602729. Epub 2016 May 17.

A Three-Site Mechanism for Agonist/Antagonist Selective Binding to Vasopressin Receptors.

Author information

1
Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstrasse 25, 91052, Erlangen, Germany.
2
Department of Chemistry and Institute of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK.
3
School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK.
4
UNICAEN, CERMN, UPRES EA 4258, FR CNRS 3038 INC3M -, Normandie Univ., Boulevard Becquerel, 14032, CAEN Cedex, France.
5
Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstrasse 25, 91052, Erlangen, Germany. Tim.Clark@fau.de.
6
School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK. Tim.Clark@fau.de.

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.

KEYWORDS:

G-protein coupled receptors; hormones; metadynamics; molecular dynamics; receptors

PMID:
27184628
DOI:
10.1002/anie.201602729
[Indexed for MEDLINE]

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