Work

Ligand-dependent G protein dynamics underlying opioid efficacy

Year: 2026

Type: article

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. Deutsch et al. show how μ-opioid receptor agonists exert long-range allosteric control over bound G proteins, providing an additional mechanism for encoding opioid signaling outcomes.

Source: Nature Structural & Molecular Biology

DOI: 10.1038/s41594-026-01893-6