2. Academic Validation
  3. Molecular mechanisms of inverse agonism via κ-opioid receptor-G protein complexes

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

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. gati@usc.edu.
  • 10 Department of Chemistry, University of Southern California, Los Angeles, CA, USA. gati@usc.edu.
  • 11 Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA. gati@usc.edu.
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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