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TitleStructural and dynamic insights into the biased signaling mechanism of the human kappa opioid receptor.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 9392, Year 2025
Publish dateOct 28, 2025
AuthorsChiyo Suno-Ikeda / Ryo Nishikawa / Riko Suzuki / Shun Yokoi / Seiya Iwata / Tomoyo Takai / Takaya Ogura / Mika Hirose / Akihisa Tokuda / Risako Katamoto / Akitoshi Inoue / Eri Asai / Ryoji Kise / Yukihiko Sugita / Takayuki Kato / Hiroshi Nagase / Ayori Mitsutake / Tsuyoshi Saitoh / Kota Katayama / Asuka Inoue / Hideki Kandori / Takuya Kobayashi / Ryoji Suno /
PubMed AbstractThe κ-opioid receptor (KOR) is a member of the G protein-coupled receptor (GPCR) family, modulating cellular responses through transducers such as G proteins and β-arrestins. G-protein-biased KOR ...The κ-opioid receptor (KOR) is a member of the G protein-coupled receptor (GPCR) family, modulating cellular responses through transducers such as G proteins and β-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 β-arrestin recruitment by nalfurafine and U-50,488H. Cryo-electron microscopy structures of the KOR-G 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, C286, H291, and Y312; Ballesteros-Weinstein numbering is shown in superscript) that play crucial roles in β-arrestin recruitment. Furthermore, MD simulations revealed that the four mutants tend to adopt conformations with reduced β-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 and Y312, which have previously been implicated in biased signaling.
External linksNat Commun / PubMed:41152269 / PubMed Central
MethodsEM (single particle)
Resolution2.76 - 2.9 Å
Structure data

64947

9v6o

EMDB-64947: Cryo-EM structure of the human kappa opioid receptor signaling complex bound to compound A
PDB-9v6o: Cryo-EM structure of human kappa opioid receptor - G protein signaling complex bound with nalfurafine.
Method: EM (single particle) / Resolution: 2.76 Å

65622

9w49

EMDB-65622, PDB-9w49:
Cryo-EM structure of human kappa opioid receptor -G protein signaling complex bound with U-50488H
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-IVB:
nalfurafine

PDB-1lwx:
AZT DIPHOSPHATE BINDING TO NUCLEOSIDE DIPHOSPHATE KINASE

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / signal transduction / GPCR / G protein / opioid receptor / balanced agonist

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