1. Academic Validation
  2. Structures of the entire human opioid receptor family

Structures of the entire human opioid receptor family

  • Cell. 2023 Jan 11;S0092-8674(22)01545-8. doi: 10.1016/j.cell.2022.12.026.
Yue Wang 1 Youwen Zhuang 2 Jeffrey F DiBerto 3 X Edward Zhou 4 Gavin P Schmitz 3 Qingning Yuan 5 Manish K Jain 3 Weiyi Liu 1 Karsten Melcher 4 Yi Jiang 6 Bryan L Roth 7 H Eric Xu 8
Affiliations

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: [email protected]
  • 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: [email protected]
  • 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: [email protected]
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-Gi 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.

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