期刊
NATURE CHEMICAL BIOLOGY
卷 18, 期 3, 页码 264-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-021-00918-z
关键词
-
资金
- National Natural Science Foundation of China [81930003, 82090012, 81922071, 81870007, 81920108001]
- Zhejiang Province National Science Fund [LR19H310001, LD19H160001]
This study identified different N-terminal truncations of endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, and revealed the structural basis of natural biased signaling that initiates an inflammation response. The structure of CCL15-bound CCR1 also showed a critical site for ligand binding distinct from many other chemokine-receptor complexes, providing new insights into the mode of chemokine recognition.
Biased signaling of G protein-coupled receptors describes an ability of different ligands that preferentially activate an alternative downstream signaling pathway. In this work, we identified and characterized different N-terminal truncations of endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, and presented three cryogenic-electron microscopy structures of the CCR1-G(i) complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6-2.9 angstrom, illustrating the structural basis of natural biased signaling that initiates an inflammation response. Complemented with pharmacological and computational studies, these structures revealed it was the conformational change of Tyr291 (Y291(7.)(43)) in CCR1 that triggered its polar network rearrangement in the orthosteric binding pocket and allosterically regulated the activation of beta-arrestin signaling. Our structure of CCL15-bound CCR1 also exhibited a critical site for ligand binding distinct from many other chemokine-receptor complexes, providing new insights into the mode of chemokine recognition.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据