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

Saleh, N; Saladino, G; Gervasio, FL; Haensele, E; Banting, L; Whitley, DC; Sopkova-de Oliveira Santos, J; ... Clark, T; + view all (2016) A Three-Site Mechanism for Agonist/Antagonist Selective Binding to Vasopressin Receptors. Angewandte Chemie , 128 (28) pp. 8140-8144. 10.1002/ange.201602729. Green open access

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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.

Type: Article
Title: A Three-Site Mechanism for Agonist/Antagonist Selective Binding to Vasopressin Receptors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/ange.201602729
Publisher version: https://doi.org/10.1002/ange.201602729
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10048283
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