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.

PMID: 34230484 DOI: 10.1038/s41467-021-24438-5

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.

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