Journal
CELL DISCOVERY
Volume 8, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41421-022-00403-4
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Funding
- National Natural Science Foundation of China [81930003, 81922071, 81870007, 81920108001, 31770796]
- Zhejiang Province National Science Fund [LR19H310001]
- Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents [2016-63]
- Ministry of Science and Technology of China [2018YFA0507002]
- Strategic Priority Research Program of Chinese Academy of Science [XDB37030103]
- Shanghai Municipal Science and Technology Major Projects [2019SHZDZX02]
- Shandong University Qilu Young Scholar [62450082163091]
- Shanghai Municipal Science and Technology Commission [19ZR1467500]
- Young Innovator Association of CAS Enrollment
- MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University
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This study presents cryo-electron microscopy structures of two human CC chemokine receptor-G-protein complexes, providing insights into the mechanisms of signal transduction and receptor activation. The findings offer important structural information and a research foundation for drug design targeting chemokine receptors.
Chemokine receptors are a family of G-protein-coupled receptors with key roles in leukocyte migration and inflammatory responses. Here, we present cryo-electron microscopy structures of two human CC chemokine receptor-G-protein complexes: CCR2 bound to its endogenous ligand CCL2, and CCR3 in the apo state. The structure of the CCL2-CCR2-G-protein complex reveals that CCL2 inserts deeply into the extracellular half of the transmembrane domain, and forms substantial interactions with the receptor through the most N-terminal glutamine. Extensive hydrophobic and polar interactions are present between both two chemokine receptors and the G alpha-protein, contributing to the constitutive activity of these receptors. Notably, complemented with functional experiments, the interactions around intracellular loop 2 of the receptors are found to be conserved and play a more critical role in G-protein activation than those around intracellular loop 3. Together, our findings provide structural insights into chemokine recognition and receptor activation, shedding lights on drug design targeting chemokine receptors.
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