Ligand-dependent G protein dynamics underlying opioid efficacy.

Higher-efficacy μ-opioid receptor agonists accelerate transitions of Gi G-protein AHD into an open, low-nucleotide-affinity conformation, despite the ligand acting over 70 Å away.

• Why it matters: Orthosteric ligands can change GPCR structure, but it remains unclear how those changes propagate to the coupled G protein to shape opioid signaling efficacy.
• What they did: Single-molecule FRET imaging tracked AHD motions in Gi proteins coupled to the μ-opioid receptor across ligand- and nucleotide-bound states, quantifying transitions among nucleotide-affinity conformations.
• The result: The ligand-dependent dynamics reveal transient AHD intermediates during nucleotide exchange and suggest that allosteric control of G-protein conformational states encodes opioid efficacy and signaling outcomes.

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