Shao Zhehua, Tan Yangxia, Shen Qingya, Hou Li, Yao Bingpeng, Qin Jiao, Xu Peiyu, Mao Chunyou, Chen Li-Nan, Zhang Huibing, Shen Dan-Dan, Zhang Chao, Li Weijie, Du Xufei, Li Fei, Chen Zhi-Hua, Jiang Yi, Xu H Eric, Ying Songmin, Ma Honglei, Zhang Yan, Shen Huahao
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, Zhejiang, China.
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Cell Discov. 2022 May 15;8(1):44. doi: 10.1038/s41421-022-00403-4.
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 Gα-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.
趋化因子受体是一类G蛋白偶联受体，在白细胞迁移和炎症反应中起关键作用。在此，我们展示了两种人类CC趋化因子受体-G蛋白复合物的冷冻电子显微镜结构：与内源性配体CCL2结合的CCR2，以及无配体状态的CCR3。CCL2-CCR2-G蛋白复合物的结构显示，CCL2深深插入跨膜结构域的细胞外部分，并通过最N端的谷氨酰胺与受体形成大量相互作用。两种趋化因子受体与Gα蛋白之间均存在广泛的疏水和极性相互作用，这有助于这些受体的组成性活性。值得注意的是，结合功能实验发现，受体细胞内环2周围的相互作用是保守的，并且在G蛋白激活中比细胞内环3周围的相互作用发挥更关键的作用。总之，我们的研究结果为趋化因子识别和受体激活提供了结构见解，为靶向趋化因子受体的药物设计提供了思路。
