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Peer-reviewedCC BY-NC-NDNature structural & molecular biology

Ligand-dependent G protein dynamics underlying opioid efficacy.

  • Jonathan C Deutsch1,2
  • Daniel Hilger3
  • John Janetzko2,4
  • Charles M Schroeder1,5,6
  • Steven Chu2,7
  • Brian K Kobilka8
  • Rabindra V Shivnaraine9,10
10 affiliations
  1. 1Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  2. 2Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
  3. 3Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany.
  4. 4Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  5. 5Departments of Materials Science and Engineering, Chemical and Biomolecular Engineering, and Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  6. 6Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA.
  7. 7Departments of Physics, Energy Sciences, and Engineering, Stanford University, Stanford, CA, USA.
  8. 8Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA. [email protected].
  9. 9Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA. [email protected].
  10. 10Aerys Biosciences, Palo Alto, CA, USA. [email protected].
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Abstract

Activation of heterotrimeric G proteins by G-protein-coupled receptors (GPCRs) requires large-scale opening of the Gα α-helical domain (AHD) to expose the nucleotide-binding site and facilitate GDP-GTP exchange. Although orthosteric ligands are known to modulate GPCR conformation, how these effects propagate to the bound G protein remains unclear. Using single-molecule Förster resonance energy transfer imaging, we monitored AHD motions in Gi proteins coupled to the μ-opioid receptor across different ligand- and nucleotide-bound states. We find that receptor ligands differentially modulate these dynamics from a binding site over 70 Å away, with higher-efficacy agonists accelerating transitions to an open, low-nucleotide-affinity conformation. These data also capture transient AHD intermediates during nucleotide exchange and suggest that allosteric control over the G protein conformational states provides an additional mechanism for encoding opioid efficacy and signaling outcomes.

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Cite

BibTeXRIS
BibTeX
@article{deutsch2026liganddependent,
  title = {{Ligand-dependent G protein dynamics underlying opioid efficacy.}},
  author = {Jonathan C Deutsch and Daniel Hilger and John Janetzko and Charles M Schroeder and Steven Chu and Brian K Kobilka and Rabindra V Shivnaraine},
  journal = {Nature structural \& molecular biology},
  year = {2026},
  month = oct,
  doi = {10.1038/s41594-026-01893-6},
  url = {https://europepmc.org/article/MED/42870023},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Ligand-dependent G protein dynamics underlying opioid efficacy.
AU  - Jonathan C Deutsch
AU  - Daniel Hilger
AU  - John Janetzko
AU  - Charles M Schroeder
AU  - Steven Chu
AU  - Brian K Kobilka
AU  - Rabindra V Shivnaraine
PY  - 2026
DA  - 2026/10/13
JO  - Nature structural & molecular biology
DO  - 10.1038/s41594-026-01893-6
UR  - https://europepmc.org/article/MED/42870023
AB  - Activation of heterotrimeric G proteins by G-protein-coupled receptors (GPCRs) requires large-scale opening of the Gα α-helical domain (AHD) to expose the nucleotide-binding site and facilitate GDP-GTP exchange. Although orthosteric ligands are known to modulate GPCR conformation, how these effects propagate to the bound G protein remains unclear. Using single-molecule Förster resonance energy transfer imaging, we monitored AHD motions in Gi proteins coupled to the μ-opioid receptor across different ligand- and nucleotide-bound states. We find that receptor ligands differentially modulate these dynamics from a binding site over 70 Å away, with higher-efficacy agonists accelerating transitions to an open, low-nucleotide-affinity conformation. These data also capture transient AHD intermediates during nucleotide exchange and suggest that allosteric control over the G protein conformational states provides an additional mechanism for encoding opioid efficacy and signaling outcomes.
SN  - 1545-9993
SN  - 1545-9985
ER  -