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GPCR activation and GRK2 assembly by a biased intracellular agonist

Author

Listed:
  • Jia Duan

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Heng Liu

    (Chinese Academy of Sciences)

  • Fenghui Zhao

    (Chinese Academy of Sciences)

  • Qingning Yuan

    (Chinese Academy of Sciences)

  • Yujie Ji

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xiaoqing Cai

    (Chinese Academy of Sciences)

  • Xinheng He

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xinzhu Li

    (Chinese Academy of Sciences)

  • Junrui Li

    (Chinese Academy of Sciences)

  • Kai Wu

    (Chinese Academy of Sciences)

  • Tianyu Gao

    (Chinese Academy of Sciences
    ShanghaiTech University)

  • Shengnan Zhu

    (Chinese Academy of Sciences)

  • Shi Lin

    (Research Center for Deepsea Bioresources)

  • Ming-Wei Wang

    (Research Center for Deepsea Bioresources)

  • Xi Cheng

    (Chinese Academy of Sciences)

  • Wanchao Yin

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yi Jiang

    (Lingang Laboratory)

  • Dehua Yang

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    Research Center for Deepsea Bioresources)

  • H. Eric Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University)

Abstract

Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands1–6. The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR–GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gαq and the arrestin-biased ligand SBI-5537. The density map reveals the arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor transmembrane helix 6, analogous to the binding of the G protein to the receptor. SBI-553 binds at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of SBI-553 is compatible with arrestin binding but clashes with the binding of Gαq protein, thus providing a mechanism for its arrestin-biased signalling capability. In sum, our structure provides a rational model for understanding the details of GPCR–GRK interactions and GRK2-mediated biased signalling.

Suggested Citation

  • Jia Duan & Heng Liu & Fenghui Zhao & Qingning Yuan & Yujie Ji & Xiaoqing Cai & Xinheng He & Xinzhu Li & Junrui Li & Kai Wu & Tianyu Gao & Shengnan Zhu & Shi Lin & Ming-Wei Wang & Xi Cheng & Wanchao Yi, 2023. "GPCR activation and GRK2 assembly by a biased intracellular agonist," Nature, Nature, vol. 620(7974), pages 676-681, August.
  • Handle: RePEc:nat:nature:v:620:y:2023:i:7974:d:10.1038_s41586-023-06395-9
    DOI: 10.1038/s41586-023-06395-9
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    Cited by:

    1. Hongmin Cai & Shimeng Guo & Youwei Xu & Jun Sun & Junrui Li & Zhikan Xia & Yi Jiang & Xin Xie & H. Eric Xu, 2024. "Cryo-EM structures of adenosine receptor A3AR bound to selective agonists," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. Yu Qian & Zhengxiong Ma & Zhenmei Xu & Yaning Duan & Yangjie Xiong & Ruixue Xia & Xinyan Zhu & Zongwei Zhang & Xinyu Tian & Han Yin & Jian Liu & Jing Song & Yang Lu & Anqi Zhang & Changyou Guo & Lihua, 2024. "Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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