8TB7

Cryo-EM Structure of GPR61-

Summary for 8TB7

• Entry DOI: 10.2210/pdb8tb7/pdb
• EMDB information: 41145
• Descriptor: G-protein coupled receptor 61,Soluble cytochrome b562, Fab24 BAK5 heavy chain, Fab hinge-binding nanobody, ... (6 entities in total)
• Functional Keywords: gpcr, inverse agonist, membrane protein, bril, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 150079.25

Authors

Lees, J.A.,Dias, J.M.,Han, S. (deposition date: 2023-06-28, release date: 2023-10-04, Last modification date: 2025-05-14)

Primary citation

Lees, J.A.,Dias, J.M.,Rajamohan, F.,Fortin, J.P.,O'Connor, R.,Kong, J.X.,Hughes, E.A.G.,Fisher, E.L.,Tuttle, J.B.,Lovett, G.,Kormos, B.L.,Unwalla, R.J.,Zhang, L.,Dechert Schmitt, A.M.,Zhou, D.,Moran, M.,Stevens, K.A.,Fennell, K.F.,Varghese, A.E.,Maxwell, A.,Cote, E.E.,Zhang, Y.,Han, S.
An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism.
Nat Commun, 14:5938-5938, 2023

PubMed Abstract: GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation.

PubMed: 37741852
DOI: 10.1038/s41467-023-41646-3

Experimental method

ELECTRON MICROSCOPY (2.94 Å)