Structural basis for chemokine recognition and receptor activation of chemokine receptor CCR5 PMID: 34230484

ADC Targets in Oncology

2026-04-10

Structural basis for chemokine recognition and receptor activation of chemokine receptor CCR5

Nat Commun. 2021 Jul 6;12(1):4151. doi: 10.1038/s41467-021-24438-5.

Hui Zhang ^# ¹ ² ³ , Kun Chen ^# ¹ ² ³ , Qiuxiang Tan ^# ¹ , Qiang Shao ^# ¹ , Shuo Han ^# ² , Chenhui Zhang ¹ ² ³ , Cuiying Yi ² , Xiaojing Chu ¹ , Ya Zhu ⁴ , Yechun Xu ⁵ ⁶ ⁷ , Qiang Zhao ⁸ ⁹ ¹⁰ ¹¹ , Beili Wu ¹² ¹³ ¹⁴ ¹⁵

Affiliations

1. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
3. University of Chinese Academy of Sciences, Beijing, China.
4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
5. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
6. University of Chinese Academy of Sciences, Beijing, China. [email protected].
7. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
8. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
9. University of Chinese Academy of Sciences, Beijing, China. [email protected].
10. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
11. Zhongshan Branch, the Institute of Drug Discovery and Development, CAS, Zhongshan, China. [email protected].
12. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
13. University of Chinese Academy of Sciences, Beijing, China. [email protected].
14. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
15. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
# Contributed equally.

Abstract

The Chemokine Receptor CCR5 plays a vital role in immune surveillance and inflammation. However, molecular details that govern its endogenous chemokine recognition and receptor activation remain elusive. Here we report three cryo-electron microscopy structures of G_i1 protein-coupled CCR5 in a ligand-free state and in complex with the chemokine MIP-1α or RANTES, as well as the crystal structure of MIP-1α-bound CCR5. These structures reveal distinct binding modes of the two chemokines and a specific accommodate pattern of the chemokine for the distal N terminus of CCR5. Together with functional data, the structures demonstrate that chemokine-induced rearrangement of toggle switch and plasticity of the receptor extracellular region are critical for receptor activation, while a conserved tryptophan residue in helix II acts as a trigger of receptor constitutive activation.