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Cryo-EM structure of endomorphin-1-muOR-arrestin2-Fab30 complex
Structural highlights
DiseaseV2R_HUMAN Nephrogenic syndrome of inappropriate antidiuresis;Inappropriate antidiuretic hormone secretion syndrome;Nephrogenic diabetes insipidus. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionOPRM_MOUSE Receptor for endogenous opioids such as beta-endorphin and endomorphin. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 9 is involved in morphine-induced scratching and seems to cross-activate GRPR in response to morphine.[1] [2] [3] [4] [5] [6] V2R_HUMAN Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption.[7] Publication Abstract from PubMedActivation 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[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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