{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Robertson MJ"],"funding":["NIGMS NIH HHS"],"pagination":["1188-1195"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12014012"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["29(12)"],"pubmed_abstract":["Cryogenic electron microscopy (cryo-EM) has widened the field of structure-based drug discovery by allowing for routine determination of membrane protein structures previously intractable. Despite representing one of the largest classes of therapeutic targets, most inactive-state G protein-coupled receptors (GPCRs) have remained inaccessible for cryo-EM because their small size and membrane-embedded nature impedes projection alignment for high-resolution map reconstructions. Here we demonstrate that the same single-chain camelid antibody (nanobody) recognizing a grafted intracellular loop can be used to obtain cryo-EM structures of inactive-state GPCRs at resolutions comparable or better than those obtained by X-ray crystallography. Using this approach, we obtained structures of neurotensin 1 receptor bound to antagonist SR48692, μ-opioid receptor bound to alvimopan, apo somatostatin receptor 2 and histamine receptor 2 bound to famotidine. We expect this rapid, straightforward approach to facilitate the broad exploration of GPCR inactive states without the need for extensive engineering and crystallization."],"journal":["Nature structural & molecular biology"],"pubmed_title":["Structure determination of inactive-state GPCRs with a universal nanobody."],"pmcid":["PMC12014012"],"funding_grant_id":["R35 GM143061","T32 GM089626"],"pubmed_authors":["Seven AB","He F","Papasergi-Scott MM","Che T","Skiniotis G","Peroto MC","Meyerowitz JG","Panova O","Robertson MJ"],"additional_accession":[]},"is_claimable":false,"name":"Structure determination of inactive-state GPCRs with a universal nanobody.","description":"Cryogenic electron microscopy (cryo-EM) has widened the field of structure-based drug discovery by allowing for routine determination of membrane protein structures previously intractable. Despite representing one of the largest classes of therapeutic targets, most inactive-state G protein-coupled receptors (GPCRs) have remained inaccessible for cryo-EM because their small size and membrane-embedded nature impedes projection alignment for high-resolution map reconstructions. Here we demonstrate that the same single-chain camelid antibody (nanobody) recognizing a grafted intracellular loop can be used to obtain cryo-EM structures of inactive-state GPCRs at resolutions comparable or better than those obtained by X-ray crystallography. Using this approach, we obtained structures of neurotensin 1 receptor bound to antagonist SR48692, μ-opioid receptor bound to alvimopan, apo somatostatin receptor 2 and histamine receptor 2 bound to famotidine. We expect this rapid, straightforward approach to facilitate the broad exploration of GPCR inactive states without the need for extensive engineering and crystallization.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2026-06-02T00:03:00.213Z","creation":"2025-07-03T03:05:07.72Z"},"accession":"S-EPMC12014012","cross_references":{"pubmed":["36396979"],"doi":["10.1038/s41594-022-00859-8"]}}