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<p>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–G<sub>i</sub> protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR–G<sub>i</sub> 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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月7日

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  • Aaliyah S. Tyson,
  • Saif Khan,
  • Zenia Motiwala,
  • Gye Won Han,
  • Zixin Zhang,
  • Mohsen Ranjbar,
  • Daniel Styrpejko,
  • Nokomis Ramos-Gonzalez,
  • Stone Woo,
  • Kelly Villers,
  • Delainey Landaker,
  • Terry Kenakin,
  • Ryan Shenvi,
  • Susruta Majumdar,
  • Cornelius Gati

摘要

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.