Related Experiment Video

Updated: Jul 6, 2025

A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4
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A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4

Published on: March 10, 2018

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

Haizhan Jiao1, Bin Pang2, Aijun Liu1

  • 1Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen, China.

Nature Structural & Molecular Biology
|January 4, 2024
PubMed

Insights

Researchers elucidated the structural basis for CXCR3 receptor activation and inhibition. Understanding these mechanisms, involving chemokines and novel agonists/antagonists, offers insights for developing new type 1 immunity drugs.

Area of Science:

  • Immunology
  • Structural Biology
  • Pharmacology

Background:

  • Chemokine receptor CXCR3 (CXC chemokine receptor 3) and its ligands (CXCL9-11) are crucial for type 1 immunity, guiding T cell migration.
  • Dysregulation of CXCR3 signaling is implicated in various immune-related diseases.

Purpose of the Study:

  • To determine the structures of human CXCR3 in complex with various agonists and an antagonist.
  • To elucidate the molecular mechanisms underlying CXCR3 activation and inhibition.

Main Methods:

  • X-ray crystallography was used to determine the structures of CXCR3 complexes.
  • Biochemical assays were employed to characterize the pharmacological properties of modulators.

Main Results:

  • Structures revealed distinct binding modes for agonists CXCL11, PS372424, and VUF11222.
  • A novel allosteric binding site for antagonist SCH546738 was identified between transmembrane helices 5 and 6.
  • SCH546738 appears to stabilize an inactive receptor conformation.

Conclusions:

  • The study provides detailed structural insights into CXCR3 activation by different classes of ligands.
  • The findings illuminate the allosteric inhibition mechanism of CXCR3.
  • This work lays the foundation for structure-based drug design targeting CXCR3 for immune modulation.

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