Structural insights into the activation and inhibition of CXC chemokine receptor 3

Haizhan Jiao; Bin Pang; Aijun Liu; Qiang Chen; Qi Pan; Xiankun Wang; Yunong Xu; Ying-Chih Chiang; Ruobing Ren; Hongli Hu

doi:10.1038/s41594-023-01175-5

Structural insights into the activation and inhibition of CXC chemokine receptor 3

Nat Struct Mol Biol. 2024 Apr;31(4):610-620. doi: 10.1038/s41594-023-01175-5. Epub 2024 Jan 4.

Authors

Haizhan Jiao^#¹, Bin Pang^#², Aijun Liu¹, Qiang Chen¹, Qi Pan^{1

3}, Xiankun Wang¹, Yunong Xu¹, Ying-Chih Chiang⁴, Ruobing Ren⁵, Hongli Hu⁶

Affiliations

¹ Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen, China.
² Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
³ School of Life and Health Sciences, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen, China.
⁴ Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen, China. chiangyc@cuhk.edu.cn.
⁵ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China. renruobing@fudan.edu.cn.
⁶ Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen, China. honglihu@cuhk.edu.cn.

^# Contributed equally.

Abstract

The chemotaxis of CD4⁺ type 1 helper cells and CD8⁺ cytotoxic lymphocytes, guided by interferon-inducible CXC chemokine 9-11 (CXCL9-11) and CXC chemokine receptor 3 (CXCR3), plays a critical role in type 1 immunity. Here we determined the structures of human CXCR3-DNG_i complexes activated by chemokine CXCL11, peptidomimetic agonist PS372424 and biaryl-type agonist VUF11222, and the structure of inactive CXCR3 bound to noncompetitive antagonist SCH546738. Structural analysis revealed that PS372424 shares a similar orthosteric binding pocket to the N terminus of CXCL11, while VUF11222 buries deeper and activates the receptor in a distinct manner. We showed an allosteric binding site between TM5 and TM6, accommodating SCH546738 in the inactive CXCR3. SCH546738 may restrain the receptor at an inactive state by preventing the repacking of TM5 and TM6. By revealing the binding patterns and the pharmacological properties of the four modulators, we present the activation mechanisms of CXCR3 and provide insights for future drug development.

MeSH terms

Binding Sites
Chemokines, CXC* / metabolism
Humans
Ligands
Protein Binding
Receptors, CXCR3* / metabolism

Substances

Receptors, CXCR3
Ligands
Chemokines, CXC