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β-arrestin1 acts as a positive regulator that holds Gαs in a signaling-competent state, providing a unifying structural basis for sustained endosomal GPCR signaling.
Findings reveal a conserved intracellular allosteric activation mechanism across multiple class B GPCRs and identify SIM1 and its analogs as valuable chemical tools for investigating receptor-specific intracellular allosteric regulation and G protein-preferential signaling.
G protein-coupled receptors (GPCRs) signal across a continuum of activation states, yet how ligands encode distinct signaling efficacies remains poorly understood. Here, we define the molecular mechanism underlying graded activation of the dopamine D1 receptor (D1R), a major therapeutic target for neuropsychiatric diso...
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