7UL3

CryoEM Structure of Inactive H2R Bound to Famotidine, Nb6M, and NabFab

Summary for 7UL3

• Entry DOI: 10.2210/pdb7ul3/pdb
• EMDB information: 26590
• Descriptor: Histamine H2 receptor, Nanobody 6M, NabFab HC, ... (5 entities in total)
• Functional Keywords: antagonist, complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 108471.81

Authors

Robertson, M.J.,Skiniotis, G. (deposition date: 2022-04-03, release date: 2022-06-29, Last modification date: 2024-10-09)

Primary citation

Robertson, M.J.,Papasergi-Scott, M.M.,He, F.,Seven, A.B.,Meyerowitz, J.G.,Panova, O.,Peroto, M.C.,Che, T.,Skiniotis, G.
Structure determination of inactive-state GPCRs with a universal nanobody.
Nat.Struct.Mol.Biol., 29:1188-1195, 2022

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.

PubMed: 36396979
DOI: 10.1038/s41594-022-00859-8

Experimental method

ELECTRON MICROSCOPY (3 Å)