7t2h | pdb_00007t2h

CryoEM structure of mu-opioid receptor - Gi protein complex bound to lofentanil (LFT)

spinqualitylabelsall models 7t2h, resolution 3.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7t2h is a 5 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.2Å Ligands: EID Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division. Publication Abstract from PubMed Drugs targeting the mu-opioid receptor (muOR) are the most effective analgesics available but are also associated with fatal respiratory depression through a pathway that remains unclear. Here we investigated the mechanistic basis of action of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two muOR agonists with different safety profiles. LFT, one of the most lethal opioids, and MP, a kratom plant derivative with reduced respiratory depression in animal studies, exhibited markedly different efficacy profiles for G protein subtype activation and beta-arrestin recruitment. Cryo-EM structures of muOR-Gi1 complex with MP (2.5 A) and LFT (3.2 A) revealed that the two ligands engage distinct subpockets, and molecular dynamics simulations showed additional differences in the binding site that promote distinct active-state conformations on the intracellular side of the receptor where G proteins and beta-arrestins bind. These observations highlight how drugs engaging different parts of the muOR orthosteric pocket can lead to distinct signaling outcomes. Insights into distinct signaling profiles of the microOR activated by diverse agonists.,Qu Q, Huang W, Aydin D, Paggi JM, Seven AB, Wang H, Chakraborty S, Che T, DiBerto JF, Robertson MJ, Inoue A, Suomivuori CM, Roth BL, Majumdar S, Dror RO, Kobilka BK, Skiniotis G Nat Chem Biol. 2023 Apr;19(4):423-430. doi: 10.1038/s41589-022-01208-y. Epub 2022 , Nov 21. PMID:36411392 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Opioid receptor Transducin 3D structures

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