Molecular mechanisms of inverse agonism via κ-opioid receptor-G protein complexes

  • Nat Chem Biol. 2025 Jan 7. doi: 10.1038/s41589-024-01812-0.
Aaliyah S Tyson  1  2 ,  Saif Khan  1  3 ,  Zenia Motiwala  1  3  4 ,  Gye Won Han  1 ,  Zixin Zhang  1  5 ,  Mohsen Ranjbar  1  2 ,  Daniel Styrpejko  1  3 ,  Nokomis Ramos-Gonzalez  6 ,  Stone Woo  7 ,  Kelly Villers  1 ,  Delainey Landaker  1 ,  Terry Kenakin  8 ,  Ryan Shenvi  7 ,  Susruta Majumdar  6 ,  Cornelius Gati  9  10  11
Affiliations
  • 1. The Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • 2. Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • 3. Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
  • 4. Amgen Inc., Thousand Oaks, CA, USA.
  • 5. Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 6. Center for Clinical Pharmacology, University of Health Sciences and Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, MO, USA.
  • 7. Department of Chemistry, Scripps Research, La Jolla, CA, USA.
  • 8. Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • 9. The Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA. [email protected].
  • 10. Department of Chemistry, University of Southern California, Los Angeles, CA, USA. [email protected].
  • 11. Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA. [email protected].
PMID: 39775170 DOI: 10.1038/s41589-024-01812-0
Abstract

Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist. The pharmacological impact of agonist-free receptor-G protein complexes is poorly understood. Here we present biochemical evidence that certain κ-opioid receptor (KOR) inverse agonists can act via KOR-Gi protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR-Gi protein complexes with three inverse agonists: JDTic, norBNI and GB18, corresponding to structures of inverse agonist-bound GPCR-G protein complexes. Remarkably, the orthosteric binding pocket resembles the G protein-free 'inactive' receptor conformation, while the receptor remains coupled to the G protein. In summary, our work challenges the canonical model of receptor antagonism and offers crucial insights into GPCR pharmacology.

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