Year: 2020
Type: article
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.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: European Commission, Deutsche Forschungsgemeinschaft, Partnership for Advanced Computing in Europe AISBL, Barcelona Supercomputing Center, Centro Svizzero di Calcolo Scientifico, National Supercomputing Centre Singapore, Horizon 2020 Framework Programme, Engineering and Physical Sciences Research Council, Leibniz-Gemeinschaft
Awards: G2087520253, The UK High-End Computing Consortium for Biomolecular Simulation, G3702480926, G3828234510, G3835265546, CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface, G4937468798, G5045220161, G5758995618, EPSRC Flagship Software - BioSimSpace: A shared space for the community development of biomolecular simulation workflows, G7941732191, Efficient modelling and validation of cryptic protein binding sites for drug discovery
OpenAlex ID: W3036901602