Structural and dynamic insights into the biased signaling mechanism of the human kappa opioid receptor.

ABSTRACT: 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_i signaling complexes identify the ligand binding mode in the activated state. Vibrational spectroscopy reveals ligand-induced conformational changes. Cell-based mutant experiments pinpoint fou

SUBMITTER: Suno-Ikeda C 

PROVIDER: S-EPMC12569041 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature