A three-site mechanism for agonist/antagonist selective binding to vasopressin receptors

Noureldin Saleh; Giorgio Saladino; Francesco L. Gervasio; Elke Haensele; Lee Banting; David C. Whitley; Jana Sopkova-de Oliveira Santos; Ronan Bureau; Timothy Clark

doi:10.1002/ange.201602729

A three-site mechanism for agonist/antagonist selective binding to vasopressin receptors

Noureldin Saleh, Giorgio Saladino, Francesco L. Gervasio, Elke Haensele, Lee Banting, David C. Whitley, Jana Sopkova-de Oliveira Santos, Ronan Bureau, Timothy Clark

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Abstract

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.

Original language	English
Pages (from-to)	8140-8144
Number of pages	5
Journal	Angewandte Chemie
Volume	128
Issue number	28
Early online date	13 May 2016
DOIs	https://doi.org/10.1002/ange.201602729
Publication status	Published - 5 Jul 2016

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10.1002/ange.201602729

A three-site mechanism
This is the peer reviewed version of the following article: N. Saleh, G. Saladino, F. L. Gervasio, E. Haensele, L. Banting, D. C. Whitley, J. Sopkova-de Oliveira Santos, R. Bureau, T. Clark, Angew. Chem. 2016, 128, 8140, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/ange.201602729/full. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Accepted author manuscript (Post-print), 771 KB

http://discovery.ucl.ac.uk/10048283

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title = "A three-site mechanism for agonist/antagonist selective binding to vasopressin receptors",

abstract = "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.",

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AU - Saleh, Noureldin

AU - Saladino, Giorgio

AU - Gervasio, Francesco L.

AU - Haensele, Elke

AU - Banting, Lee

AU - Whitley, David C.

AU - Sopkova-de Oliveira Santos, Jana

AU - Bureau, Ronan

AU - Clark, Timothy

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Y1 - 2016/7/5

N2 - 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.

AB - 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.

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DO - 10.1002/ange.201602729

M3 - Article

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JO - Angewandte Chemie

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A three-site mechanism for agonist/antagonist selective binding to vasopressin receptors

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