Tyson Aaliyah S, Khan Saif, Motiwala Zenia, Han Gye Won, Zhang Zixin, Ranjbar Mohsen, Styrpejko Daniel, Ramos-Gonzalez Nokomis, Woo Stone, Villers Kelly, Landaker Delainey, Kenakin Terry, Shenvi Ryan, Majumdar Susruta, Gati Cornelius
The Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
Nat Chem Biol. 2025 Jan 7. doi: 10.1038/s41589-024-01812-0.
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 protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR-G 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.
阿片受体是G蛋白偶联受体（GPCRs）的一个亚家族，是关键的治疗靶点。在经典的GPCR激活模型中，受体与G蛋白复合物的形成需要激动剂结合，而拮抗剂则阻止G蛋白偶联。然而，许多GPCRs表现出基础活性，允许在没有激动剂的情况下发生G蛋白结合。无激动剂的受体-G蛋白复合物的药理作用尚不清楚。在此，我们提供生化证据表明，某些κ-阿片受体（KOR）反向激动剂可通过KOR-G蛋白复合物发挥作用。为了研究这一现象，我们确定了KOR-G蛋白复合物与三种反向激动剂（JDTic、norBNI和GB18）的冷冻电镜结构，这些结构对应于反向激动剂结合的GPCR-G蛋白复合物的结构。值得注意的是，正构结合口袋类似于无G蛋白的“无活性”受体构象，而受体仍与G蛋白偶联。总之，我们的工作挑战了受体拮抗的经典模型，并为GPCR药理学提供了重要见解。
