Ligand and G-protein selectivity in the κ-opioid receptor

Jianming Han, Jingying Zhang, Antonina L. Nazarova, Sarah M. Bernhard, Brian E. Krumm, Lei Zhao, Jordy Homing Lam, Vipin A. Rangari, Susruta Majumdar, David E. Nichols, Vsevolod Katritch, Peng Yuan, Jonathan F. Fay () and Tao Che ()
Additional contact information
Jianming Han: Washington University in St Louis
Jingying Zhang: Washington University School of Medicine
Antonina L. Nazarova: University of Southern California
Sarah M. Bernhard: Washington University in St Louis
Brian E. Krumm: University of North Carolina School of Medicine
Lei Zhao: Washington University in St Louis
Jordy Homing Lam: University of Southern California
Vipin A. Rangari: University of Health Sciences and Pharmacy in St Louis and Washington University School of Medicine
Susruta Majumdar: Washington University in St Louis
David E. Nichols: University of North Carolina
Vsevolod Katritch: University of Southern California
Peng Yuan: Washington University School of Medicine
Jonathan F. Fay: University of Maryland Baltimore
Tao Che: Washington University in St Louis

Nature, 2023, vol. 617, issue 7960, 417-425

Abstract: Abstract The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders1. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects2. The initiation of KOR signalling requires the Gi/o-family proteins including the conventional (Gi1, Gi2, Gi3, GoA and GoB) and nonconventional (Gz and Gg) 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—Gi1, GoA, Gz and Gg—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 Gi/o-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.

Date: 2023
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DOI: 10.1038/s41586-023-06030-7

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