Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1

• DOI: 10.1038/s41589-021-00918-z
• Publication Date: 2021-12-23T17:03:07Z
• Authors: 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
• Keywords: CCR1

Abstract Biased signaling of G protein-coupled receptors describes an ability different ligands that preferentially activate alternative downstream pathway. In this work, we identified and characterized N-terminal truncations endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, presented three cryogenic-electron microscopy structures the CCR1–G i complex in ligand-free form bound to with a resolution 2.6–2.9 Å, illustrating structural basis natural initiates inflammation response. Complemented pharmacological computational studies, these revealed it was conformational change Tyr291 (Y291 7.43 ) CCR1 triggered its polar network rearrangement orthosteric binding pocket allosterically regulated activation β-arrestin signaling. Our structure CCL15-bound also exhibited critical site for ligand distinct from many other chemokine–receptor complexes, providing new insights into mode recognition.