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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Structure-function relationship between the human chemokine receptor CXCR3 and its ligands
Ian Clark-Lewis1, Ivan Mattioli, Jiang-Hong Gong
1Biomedical Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. ian@brc.ubc.ca
The Journal of Biological Chemistry
|November 6, 2002
Summary
Researchers identified a CXCR3 antagonist by modifying I-TAC, a potent chemokine. They also found that specific regions of chemokines like I-TAC and IP10 determine their activity and binding affinity.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- Interferon-gamma inducible CXC chemokines (I-TAC, IP10, Mig) bind to the G-protein-coupled receptor CXCR3.
- CXCR3 is primarily found on Th1 lymphocytes, playing a role in immune responses.
Purpose of the Study:
- To investigate the structure-function relationships of CXCR3 ligands, focusing on I-TAC.
- To develop a potent antagonist for CXCR3 and identify regions responsible for ligand activity.
Main Methods:
- NH(2)-terminal truncation of I-TAC to create an antagonist.
- Generation of hybrid chemokines by swapping regions between I-TAC and IP10.
- Structure-activity relationship studies on Mig.
Main Results:
- I-TAC (4-73), a truncated form of I-TAC, acts as a CXCR3 antagonist without agonistic effects.
- Specific regions, including the NH(2) terminus and N-loop, are responsible for the differential activity of I-TAC and IP10.
- The extended COOH-terminal region of Mig is crucial for its binding and activity.
Conclusions:
- CXCR3 ligand function is determined by distinct, interchangeable regions.
- Truncated I-TAC provides a potent antagonist for CXCR3.
- Understanding these structure-activity relationships can inform the development of targeted immunomodulatory therapies.
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