9v6o
Cryo-EM structure of human kappa opioid receptor - G protein signaling complex bound with nalfurafine.
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedThe kappa-opioid receptor (KOR) is a member of the G protein-coupled receptor (GPCR) family, modulating cellular responses through transducers such as G proteins and beta-arrestins. G-protein-biased KOR agonists aim to retain analgesic and antipruritic actions while limiting aversion and sedation. Aiming to inform G-biased KOR agonist design, we analyze signaling-relevant residues from structural and dynamic views. Here we show, using multiple complementary methods, shared residues that determine beta-arrestin recruitment by nalfurafine and U-50,488H. Cryo-electron microscopy structures of the KOR-G(i) signaling complexes identify the ligand binding mode in the activated state. Vibrational spectroscopy reveals ligand-induced conformational changes. Cell-based mutant experiments pinpoint four amino acids (K227(5.40), C286(6.47), H291(6.52), and Y312(7.34); Ballesteros-Weinstein numbering is shown in superscript) that play crucial roles in beta-arrestin recruitment. Furthermore, MD simulations revealed that the four mutants tend to adopt conformations with reduced beta-arrestin recruitment activity. Our research findings provide a foundation for enhancing KOR-mediated therapeutic effects while minimizing unwanted side effects by targeting specific residues within the KOR ligand-binding pocket, including K227(5.40) and Y312(7.34), which have previously been implicated in biased signaling. Structural and dynamic insights into the biased signaling mechanism of the human kappa opioid receptor.,Suno-Ikeda C, Nishikawa R, Suzuki R, Yokoi S, Iwata S, Takai T, Ogura T, Hirose M, Tokuda A, Katamoto R, Inoue A, Asai E, Kise R, Sugita Y, Kato T, Nagase H, Mitsutake A, Saitoh T, Katayama K, Inoue A, Kandori H, Kobayashi T, Suno R Nat Commun. 2025 Oct 28;16(1):9392. doi: 10.1038/s41467-025-64882-1. PMID:41152269[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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