Structural basis of PTH1R-β-arrestin core engagement reveals design principles for G-protein-biased therapeutics.

G-protein-coupled receptors (GPCRs) transmit cellular signals through both G protein and arrestin pathways and biased signaling offers potential therapeutic advantages through selective activation. Although GPCR-G protein complexes are well characterized, structural understanding of class B GPCR-arrestin interactions remains limited. Here we show the cryo-electron microscopy structure of parathyroid hormone receptor 1 in core engagement with β-arrestin 1, revealing the molecular basis of arrestin coupling. The structure shows a rearrangement in which inward movement of extracellular transmembrane helix 5 (TM5) and extracellular loop 3 (ECL3) drives outward displacement of cytoplasmic TM5, forming a configuration required for arrestin binding. Guided by comparison with the Gs-coupled state, we designed peptide analogs that prevent these TM5/ECL3 conformational changes, producing G-protein-biased agonists that preserve agonist efficacy while reducing arrestin recruitment. In an ovariectomized mouse model, a lead compound shows comparable therapeutic efficacy, providing a framework for structure-guided design of biased therapeutics targeting class B GPCRs.