Structure-function relationship between the human chemokine receptor CXCR3 and its ligands

J Biol Chem. 2003 Jan 3;278(1):289-95. doi: 10.1074/jbc.M209470200. Epub 2002 Nov 1.


I-TAC, IP10, and Mig are interferon-gamma inducible CXC chemokines that share the same G-protein-coupled receptor CXCR3, which is preferentially expressed on Th1 lymphocytes. We have explored the structure-function relationship of the CXCR3 ligands, in particular of I-TAC, which has highest affinity for CXCR3 and is the most potent agonist. A potent antagonist for CXCR3 was obtained by NH(2)-terminal truncation of I-TAC. I-TAC (4-73), which lacks the first three residues, has no agonistic activity but competes for the binding of I-TAC to CXCR3-bearing cells and inhibits migration and Ca(2+) changes in such cells in response to stimulation with I-TAC, IP10, and Mig. It does also not induce internalization of CXCR3, which is in support of the lack of agonistic effects. Hybrid chemokines between I-TAC and IP10 were used to identify regions responsible for the higher activity of I-TAC. I-TAC-like IP10 analogs are obtained by substituting the NH(2) terminus (residues 1-8) or N-loop region (residues 12-17) of IP10 with those of I-TAC, suggesting that the differences in function of the CXCR3 ligands can be assigned to distinct regions and that these regions are interchangeable. Structure-activity studies with Mig showed that the extended basic COOH-terminal region, which is not present in I-TAC and IP10, is important for binding and activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Calcium / metabolism
  • Cell Line
  • Cells, Cultured
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Chemokines, CXC / chemistry
  • Chemokines, CXC / genetics
  • Chemokines, CXC / metabolism*
  • Chemotaxis / physiology
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / metabolism
  • Ligands
  • Molecular Sequence Data
  • Protein Binding
  • Radioligand Assay
  • Receptors, CXCR3
  • Receptors, Chemokine / antagonists & inhibitors
  • Receptors, Chemokine / chemistry
  • Receptors, Chemokine / metabolism*
  • Sequence Alignment
  • Structure-Activity Relationship


  • CXCL11 protein, human
  • CXCL9 protein, human
  • CXCR3 protein, human
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Chemokines, CXC
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Receptors, CXCR3
  • Receptors, Chemokine
  • Calcium