9ODL
Structure of the MOR/Gi/Mitragynine Pseudoindoxil Complex, GTP-bound G-ACT-3
Summary for 9ODL
| Entry DOI | 10.2210/pdb9odl/pdb |
| EMDB information | 70366 |
| Descriptor | Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (7 entities in total) |
| Functional Keywords | gpcr, complex, agonist, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 134820.01 |
| Authors | |
| Primary citation | Robertson, M.J.,Modak, A.,Papasergi-Scott, M.M.,Hu, M.,Peroto, M.C.,Varga, B.R.,Majumdar, S.,Kalathur, R.,Blanchard, S.C.,Skiniotis, G. Non-equilibrium snapshots of ligand efficacy at the mu-opioid receptor. Nature, 2025 Cited by PubMed Abstract: 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 Gαiβγ heterotrimer by the μ-opioid receptor (MOR) bound to three ligands displaying partial, full, or super-agonism on the receptor. 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. PubMed: 41430437DOI: 10.1038/s41586-025-10056-4 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.6 Å) |
Structure validation
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