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:
- 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.
- 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.
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