{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Latorraca NR"],"funding":["NIMH NIH HHS","NINDS NIH HHS","NIGMS NIH HHS"],"pubmed_abstract":["The G protein-coupled metabotropic glutamate receptors form homodimers and heterodimers with highly diverse responses to glutamate and varying physiological function. The molecular basis for this diversity remains poorly delineated. We employ molecular dynamics, single-molecule spectroscopy, and hydrogen-deuterium exchange to dissect the pathway of activation triggered by glutamate. We find that activation entails multiple loosely coupled steps and identify a novel pre-active intermediate whose transition to the active state forms dimer interactions that set signaling efficacy. Such subunit interactions generate functional diversity that differs across homodimers and heterodimers. The agonist-bound receptor is remarkably dynamic, with low occupancy of G protein-coupling conformations, providing considerable headroom for modulation of the landscape by allosteric ligands. Sites of sequence diversity within the dimerization interface and diverse coupling between activation rearrangements may contribute to precise decoding of glutamate signals and transients over broad spatial and temporal scales."],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2024.02.28.582567"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10925283"],"repository":["biostudies-literature"],"pubmed_title":["Domain coupling in activation of a family C GPCR."],"pmcid":["PMC10925283"],"funding_grant_id":["R01 GM116961","R01 NS119826","R35 GM149319","K99 GM148823","RF1 MH123246"],"pubmed_authors":["Habrian C","Isacoff EY","Marqusee S","Bleier J","Sabaat S","Stanley C","Latorraca NR"],"additional_accession":[]},"is_claimable":false,"name":"Domain coupling in activation of a family C GPCR.","description":"The G protein-coupled metabotropic glutamate receptors form homodimers and heterodimers with highly diverse responses to glutamate and varying physiological function. The molecular basis for this diversity remains poorly delineated. We employ molecular dynamics, single-molecule spectroscopy, and hydrogen-deuterium exchange to dissect the pathway of activation triggered by glutamate. We find that activation entails multiple loosely coupled steps and identify a novel pre-active intermediate whose transition to the active state forms dimer interactions that set signaling efficacy. Such subunit interactions generate functional diversity that differs across homodimers and heterodimers. The agonist-bound receptor is remarkably dynamic, with low occupancy of G protein-coupling conformations, providing considerable headroom for modulation of the landscape by allosteric ligands. Sites of sequence diversity within the dimerization interface and diverse coupling between activation rearrangements may contribute to precise decoding of glutamate signals and transients over broad spatial and temporal scales.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2025-04-04T19:15:44.317Z","creation":"2025-04-04T19:15:44.317Z"},"accession":"S-EPMC10925283","cross_references":{"pubmed":["38464305"],"doi":["10.1101/2024.02.28.582567"]}}