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TitleNon-equilibrium snapshots of ligand efficacy at the μ-opioid receptor.
Journal, issue, pagesNature, Year 2025
Publish dateDec 22, 2025
AuthorsMichael J Robertson / Arnab Modak / Makaía M Papasergi-Scott / Miaohui Hu / Maria Claudia Peroto / Balazs R Varga / Susruta Majumdar / Ravi Kalathur / Scott C Blanchard / Georgios Skiniotis /
PubMed AbstractDistinct ligands for the same G-protein-coupled receptor (GPCR) activate intracellular signalling partners to varying extents, but the molecular mechanisms that drive these differences remain elusive. ...Distinct ligands for the same G-protein-coupled receptor (GPCR) activate intracellular signalling partners to varying extents, but the molecular mechanisms that drive these differences remain elusive. Here, hypothesizing that such differences in signalling efficacy might be captured structurally in intermediate states under non-equilibrium conditions, we use a time-resolved cryo-electron-microscopy approach to visualize the GTP-induced activation of the Gαβγ heterotrimer by the μ-opioid receptor bound to three ligands that show partial, full or super agonism on the receptor. We resolve ensembles of conformational states along the G-protein activation pathway, including an intermediate state that enables us to visualize receptor dynamics as a function of bound ligand. The results reveal ligand-dependent differences in state occupancy and conformational stability, with higher ligand efficacy correlating with increased dynamics of the receptor's transmembrane helices 5 and 6. Furthermore, we identify key differences between G and G in the mechanism of GTP-induced activation, which are likely to underlie the distinct activation kinetics of these G-protein types. Corroborated by molecular-dynamics simulations and single-molecule fluorescence assays, our findings provide a dynamic structural landscape of GPCR-G-protein interactions for ligands of various efficacies, and suggest that partial agonists produce a 'kinetic trap' during G-protein activation.
External linksNature / PubMed:41430437
MethodsEM (single particle)
Resolution3.0 - 6.5 Å
Structure data

70364

9odj

EMDB-70364, PDB-9odj:
Structure of the MOR/Gi/Mitragynine Pseudoindoxil Complex, GTP-bound G-Primed, AHD 3DVA Sorted
Method: EM (single particle) / Resolution: 3.0 Å

70365

9odk

EMDB-70365, PDB-9odk:
Structure of the MOR/Gi/Mitragynine Pseudoindoxil Complex, GTP-bound G-ACT-2
Method: EM (single particle) / Resolution: 3.9 Å

70366

9odl

EMDB-70366, PDB-9odl:
Structure of the MOR/Gi/Mitragynine Pseudoindoxil Complex, GTP-bound G-ACT-3
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-70373: Structure of the MOR/Gi/DAMGO Complex, GTP-Bound, G-ACT-1
Method: EM (single particle) / Resolution: 6.5 Å

EMDB-70374: Structure of the MOR/Gi/DAMGO Complex, GTP-Bound, G-ACT-2/3 Consensus Refinement
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

ChemComp-EIG:
Mitragynine pseudoindoxyl

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / Complex / Agonist

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