The recruitment of β-arrestin (βarr) by G-protein-coupled receptor (GPCR) holds imperative importance in physiological processes, while the mechanisms underlying arrestin engagement with receptors remain obscure. The parathyroid hormone type 1 receptor (PTH1R), as a prototypical class B1 receptor, incorporates arrestin for signaling and regulates G-protein signaling by distinct mechanisms. Here, we report three cryo-electron microscopy structures of β-arrestin1 (βarr1) engaged with the activated wild-type and chimeric PTH1R in core conformation, revealing a distinctive binding mode of βarr1 coupling to PTH1R compared to other GPCRs. In addition to the pronounced kinking of transmembrane (TM) 6, βarr1 establishes extensive interactions with the core cavity of PTH1R by promoting the outward movement of TM5 and intracellular loop (ICL) 2, stabilizing the core conformation of the complex. Further, our work shows that the core coupling mode of βarr with PTH1R mediates receptor internalization and trafficking. Collectively, our work offers a paradigm for the arrestin coupling to class B1 GPCR and regulating the signaling transduction.
Zhai et al. (2026) studied this question.