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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 signaling partners to varying extents, but the molecular mechanisms driving these differences remain elusive. ...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.
External linksNature / PubMed:41430437
MethodsEM (single particle)
Resolution3.0 - 3.9 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

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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