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Publication Abstract from PubMed

Activation of the mu-opioid receptor (muOR) alleviates pain but also elicits adverse effects through diverse G proteins and beta-arrestins. The structural details of muOR complexes with G(z) and beta-arrestins have not been determined, impeding a comprehensive understanding of muOR signaling plasticity. Here, we present the cryo-EM structures of the muOR-G(z) and muOR-betaarr1 complexes, revealing selective conformational preferences of muOR 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 muOR signaling bias through differential stabilization of the G(i)-, G(z)-, and betaarr1-bound states. Mechanistically, outward TM1 displacement confers structural flexibility that promotes G protein recruitment, whereas inward TM1 retraction facilitates betaarr1 recruitment by stabilizing the intracellular binding pocket through coordinated interactions with TM2, TM7, and helix8. Structural comparisons between the G(i)-, G(z)-, and betaarr1-bound complexes identified a TM1-fusion pocket with significant implications for downstream signaling regulation. Overall, we demonstrate that the conformational and thermodynamic heterogeneity of TM1 allosterically drives the downstream signaling specificity and plasticity of muOR, thereby expanding the understanding of muOR signal transduction mechanisms and providing new avenues for the rational design of analgesics.

The molecular basis of mu-opioid receptor signaling plasticity.,Zhang H, Wang X, Xi K, Shen Q, Xue J, Zhu Y, Zang SK, Yu T, Shen DD, Guo J, Chen LN, Ji SY, Qin J, Dong Y, Zhao M, Yang M, Wu H, Yang G, Zhang Y Cell Res. 2025 Nov 7. doi: 10.1038/s41422-025-01191-8. PMID:41199005^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.