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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.
Dopamine receptors (DRs) mediate central and peripheral dopaminergic signaling and remain major therapeutic targets in movement disorders, psychiatric disease, and endocrine dysfunction. Despite decades of clinical use, existing DR-directed therapies still suffer from limited subtype selectivity, pathway-nonspecific en...
Recent structural, biochemical, and physiological insights are synthesized to outline how arrestins decode regulatory inputs into signaling outcomes and how this knowledge enables the development of next-generation, structure-guided GPCR therapeutics.
Fourteen TAAR1 agonists emerge with high brain exposure and potencies, with one compound showing potency comparable to the investigational drug ulotaront and two compounds exhibiting even greater potency, at levels sufficient for behavioral studies.
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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