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Cryo-EM structure and biochemical analysis of human chemokine receptor CCR8

de Qi Peng, Haihai Jiang, Xinyu Cheng, Na Wang, Sili Zhou, Yuting Zhang, Tingting Yang, Yixiang Chen, Wei Zhang, Sijia Lv, Weiwei Nan, JianFei Wang, Guo-Huang Fan, Jian Li e Jin Zhang

Publicado: 1 de janeiro de 2024
Servidor: bioRxiv
DOI: 10.1101/2023.12.30.573520

Resumo

The C-C motif chemokine receptor 8 (CCR8) is a class A G-protein coupled receptor that has emerged as a promising therapeutic target in cancer and autoimmune diseases. Although the structures of human CCR8 in complex an antagonist antibody Fab1 and an endogenous agonist ligand CCL1 have been solved, the structure of ligand-free CCR8 remains to be determined. Here, we solved the cryo-electron microscopy (cryo-EM) structure of the human CCR8-G _i complex in the absence of a ligand. Structural analysis and comparison revealed that CCR8 in our apo structure undergoes some conformational change and is similar to that in the CCL1-CCR8 complex structure, indicating an active state. In addition, the key residues of CCR8 involved in the recognition of LMD-009, a potent nonpeptidic agonist, were investigated by mutating CCR8 and testing the calcium flux induced by LMD-009-CCR8 interaction. Two mutants of CCR8, Y113 ^3.32 A, and E286 ^7.39 A, showed a dramatically decreased ability in mediating calcium mobilization, indicating their key interaction with LMD-009. These structural and biochemical analyses provided molecular insights into the agonism and activation of CCR8 and will also facilitate CCR8-targeted therapy.

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Avaliação PREreview feita por Philipp Ross et al. do/a HHMI Transparent and Accountable Peer Review Training Program

De autoria de Philipp Ross, William Grubbe e 1 outro autor do/a HHMI Transparent and Accountable Peer Review Training Program

Summary: In this work, Peng et al present the previously unsolved apo structure of the C-C motif chemokine receptor 8 (CCR8). CCR8 is a G-protein coupled receptor (GPCR) and a potential therapeutic target for treating some cancers and autoimmune diseases. Previous structural studies of this…

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Avaliações PREreview de Cryo-EM structure and biochemical analysis of human chemokine receptor CCR8

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