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<p>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.</p>

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Core conformation of arrestin coupling to parathyroid hormone type 1 receptor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月25日

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  • Xiuwen Zhai,
  • Jia Guo,
  • Qingya Shen,
  • Li-Nan Chen,
  • Gang Wang,
  • Dan-Dan Shen,
  • Changming Zhang,
  • Xiaodong Xu,
  • Chunyou Mao,
  • Yan Zhang,
  • Zhihong Liu

摘要

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.