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

Autor: Shao Z; Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China., Shen Q; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China., Yao B; Department of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, China., Mao C; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China., Chen LN; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China., Zhang H; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China., Shen DD; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China., Zhang C; Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.; Department of Anatomy, Zhejiang University School of Medicine, Hangzhou, China., Li W; Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China., Du X; Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China., Li F; Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China., Ma H; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China., Chen ZH; Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China., Xu HE; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China.; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Ying S; Department of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, China. yings@zju.edu.cn.; International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China. yings@zju.edu.cn., Zhang Y; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. zhang_yan@zju.edu.cn.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. zhang_yan@zju.edu.cn.; Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou, China. zhang_yan@zju.edu.cn.; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, China. zhang_yan@zju.edu.cn., Shen H; Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. huahaoshen@zju.edu.cn.; State Key Laboratory of Respiratory Disease, Guangzhou, China. huahaoshen@zju.edu.cn.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2022 Mar; Vol. 18 (3), pp. 264-271. Date of Electronic Publication: 2021 Dec 23.
DOI: 10.1038/s41589-021-00918-z
Abstrakt: 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 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 7.43 ) 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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