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A combined activation mechanism for the glucagon receptor

Mattedi, G; Acosta-Gutiérrez, S; Clark, T; Gervasio, FL; (2020) A combined activation mechanism for the glucagon receptor. Proceedings of the National Academy of Sciences of the United States of America (PNAS) , 117 (27) pp. 15414-15422. 10.1073/pnas.1921851117. Green open access

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Abstract

We report on a combined activation mechanism for a class B G-protein-coupled receptor (GPCR), the glucagon receptor. By computing the conformational free-energy landscape associated with the activation of the receptor-agonist complex and comparing it with that obtained with the ternary complex (receptor-agonist-G protein) we show that the agonist stabilizes the receptor in a preactivated complex, which is then fully activated upon binding of the G protein. The proposed mechanism contrasts with the generally assumed GPCR activation mechanism, which proceeds through an opening of the intracellular region allosterically elicited by the binding of the agonist. The mechanism found here is consistent with electron cryo-microscopy structural data and might be general for class B GPCRs. It also helps us to understand the mode of action of the numerous allosteric antagonists of this important drug target.

Type: Article
Title: A combined activation mechanism for the glucagon receptor
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1921851117
Publisher version: https://doi.org/10.1073/pnas.1921851117
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: GPCR, activation, enhanced sampling, glucagon receptor
UCL classification: UCL
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/10105533
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