9odj | pdb_00009odj

Structure of the MOR/Gi/Mitragynine Pseudoindoxil Complex, GTP-bound G-Primed, AHD 3DVA Sorted

spinqualitylabelsall models 9odj, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9odj is a 4 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 3Å Ligands: CLR, EIG, GTP, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. Publication Abstract from PubMed Distinct ligands for the same G-protein coupled receptor (GPCR) activate intracellular signaling partners to varying extents, but the molecular mechanisms driving these differences remain elusive. Hypothesizing that such differences in signaling efficacy may be captured structurally in intermediate states under non-equilibrium conditions, we implemented a time-resolved (TR) cryo-EM approach to visualize the GTP-induced activation of the Galphaibetagamma heterotrimer by the mu-opioid receptor (MOR) bound to three ligands displaying partial, full, or super-agonism on the receptor(1). We resolved ensembles of conformational states along the G-protein activation pathway, including a previously unobserved intermediate state that enabled us to visualize receptor dynamics as a function of bound ligand. The results demonstrate ligand-dependent differences in state occupancy and conformational stability, with higher ligand efficacy correlating with increased dynamics of the receptor's transmembrane (TM) helices 5 and 6. Furthermore, we identify key mechanistic differences in the GTP-induced activation of Gi compared to Gs that likely underlie their distinct activation kinetics. Corroborated by molecular dynamics (MD) simulations and single-molecule fluorescence assays, these findings provide a dynamic structural landscape of GPCR-G-protein interactions for ligands of different efficacy and suggest partial agonists may produce a 'kinetic trap' during G-protein activation. Non-equilibrium snapshots of ligand efficacy at the mu-opioid receptor.,Robertson MJ, Modak A, Papasergi-Scott MM, Hu M, Peroto MC, Varga BR, Majumdar S, Kalathur R, Blanchard SC, Skiniotis G Nature. 2025 Dec 22. doi: 10.1038/s41586-025-10056-4. PMID:41430437 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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