8DZR

GR89,696 bound Kappa Opioid Receptor in complex with gustducin

Summary for 8DZR

• Entry DOI: 10.2210/pdb8dzr/pdb
• EMDB information: 27804 27805 27806 27807
• Descriptor: Kappa-type opioid receptor, G alpha gustducin protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: gpcr, kappa opioid receptor, g protein, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 144871.21

Authors

Fay, J.F.,Che, T. (deposition date: 2022-08-08, release date: 2023-05-03, Last modification date: 2025-05-14)

Primary citation

Han, J.,Zhang, J.,Nazarova, A.L.,Bernhard, S.M.,Krumm, B.E.,Zhao, L.,Lam, J.H.,Rangari, V.A.,Majumdar, S.,Nichols, D.E.,Katritch, V.,Yuan, P.,Fay, J.F.,Che, T.
Ligand and G-protein selectivity in the kappa-opioid receptor.
Nature, 617:417-425, 2023

PubMed Abstract: The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects. The initiation of KOR signalling requires the G-family proteins including the conventional (G, G, G, G and G) and nonconventional (G and G) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers-G, G, G and G-using cryo-electron microscopy. The KOR-G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR-G-protein interactions as well as key elements governing G-family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.

PubMed: 37138078
DOI: 10.1038/s41586-023-06030-7

Experimental method

ELECTRON MICROSCOPY (2.61 Å)