The molecular basis of μ-opioid receptor signaling plasticity.

ABSTRACT: Activation of the μ-opioid receptor (μOR) alleviates pain but also elicits adverse effects through diverse G proteins and β-arrestins. The structural details of μOR complexes with G_z and β-arrestins have not been determined, impeding a comprehensive understanding of μOR signaling plasticity. Here, we present the cryo-EM structures of the μOR-G_z and μOR-βarr1 complexes, revealing selective conformational preferences of μOR when engaged with specific downstream signaling transducers. Integrated receptor pharmacology, including high-resolution structural analysis, cell signaling assays, and molecular dynamics simulations, demonstrated that transmembrane helix 1 (TM1) acts as an allosteric regulator of μOR signaling bias through differential stabilization of the G_i</

SUBMITTER: Zhang H 

PROVIDER: S-EPMC12689640 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature