Structures of the entire human opioid receptor family

Yue Wang; Youwen Zhuang; Jeffrey F DiBerto; X Edward Zhou; Gavin P Schmitz; Qingning Yuan; Manish K Jain; Weiyi Liu; Karsten Melcher; Yi Jiang; Bryan L Roth; H Eric Xu

doi:10.1016/j.cell.2022.12.026

Structures of the entire human opioid receptor family

Cell. 2023 Jan 19;186(2):413-427.e17. doi: 10.1016/j.cell.2022.12.026. Epub 2023 Jan 12.

Authors

Yue Wang¹, Youwen Zhuang², Jeffrey F DiBerto³, X Edward Zhou⁴, Gavin P Schmitz³, Qingning Yuan⁵, Manish K Jain³, Weiyi Liu¹, Karsten Melcher⁴, Yi Jiang⁶, Bryan L Roth⁷, H Eric Xu⁸

Affiliations

¹ The CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² The CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: zhuangyouwen@simm.ac.cn.
³ Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
⁴ Department of Structural Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁵ The CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁶ The CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Lingang Laboratory, Shanghai 200031, China.
⁷ Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: bryan_roth@med.unc.edu.
⁸ The CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: eric.xu@simm.ac.cn.

PMID: 36638794
DOI: 10.1016/j.cell.2022.12.026

Abstract

Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid crisis. The human opioid system contains four opioid receptors (μOR, δOR, κOR, and NOPR) and a set of related endogenous opioid peptides (EOPs), which show distinct selectivity toward their respective opioid receptors (ORs). Despite being key to the development of safer analgesics, the mechanisms of molecular recognition and selectivity of EOPs to ORs remain unclear. Here, we systematically characterize the binding of EOPs to ORs and present five structures of EOP-OR-G_i complexes, including β-endorphin- and endomorphin-bound μOR, deltorphin-bound δOR, dynorphin-bound κOR, and nociceptin-bound NOPR. These structures, supported by biochemical results, uncover the specific recognition and selectivity of opioid peptides and the conserved mechanism of opioid receptor activation. These results provide a structural framework to facilitate rational design of safer opioid drugs for pain relief.

Keywords: GPCRs; analgesics; deltorphin; dynorphin; endogenous opioid peptides; endomorphin; endorphin; ligand selectivity; nociceptin; opioid receptors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Analgesics, Opioid / pharmacology
Humans
Opioid Peptides
Receptors, Opioid* / chemistry
Receptors, Opioid, mu / metabolism

Substances

Analgesics, Opioid
Opioid Peptides
Receptors, Opioid, mu
Receptors, Opioid