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-Structure paper
Title | Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1. |
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Journal, issue, pages | Nat Chem Biol, Vol. 18, Issue 3, Page 264-271, Year 2022 |
Publish date | Dec 23, 2021 |
![]() | Zhehua Shao / Qingya Shen / Bingpeng Yao / Chunyou Mao / Li-Nan Chen / Huibing Zhang / Dan-Dan Shen / Chao Zhang / Weijie Li / Xufei Du / Fei Li / Honglei Ma / Zhi-Hua Chen / H Eric Xu / Songmin Ying / Yan Zhang / Huahao Shen / ![]() |
PubMed Abstract | 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 ...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 complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6-2.9 Å, 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) in CCR1 that triggered its polar network rearrangement in the orthosteric binding pocket and allosterically regulated the activation of β-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. |
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Methods | EM (single particle) |
Resolution | 2.6 - 2.9 Å |
Structure data | EMDB-32020, PDB-7vl8: EMDB-32021, PDB-7vl9: EMDB-32022, PDB-7vla: |
Chemicals | ![]() ChemComp-CLR: |
Source |
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![]() | MEMBRANE PROTEIN / GPCR / CCR1 / Chemokine Receptor / MEMBRNE PROTEIN |