Structure of mouse IP-10, a chemokine
Talat Jabeen1, Philip Leonard, Haryati Jamaluddin
1Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, England.
Insights
The crystal structure of mouse Interferon-gamma-inducible protein (IP-10) reveals a novel tetrameric association, differing from human IP-10 structures. This finding is crucial for understanding IP-10
Area of Science:
- Structural Biology
- Immunology
- Biochemistry
Background:
- Interferon-gamma-inducible protein (IP-10) is a CXC chemokine involved in immune and inflammatory responses.
- IP-10 acts as an angiostatic and antifibrotic factor.
- Its biological activities are mediated through the CXCR3 receptor on Th1 lymphocytes.
Purpose of the Study:
- To determine the crystal structure of mouse IP-10.
- To elucidate the structural basis for IP-10's biological activities.
- To provide insights for structure-based drug design of anti-inflammatory molecules.
Main Methods:
- X-ray crystallography was used to determine the crystal structure of mouse IP-10.
- Analysis of the tetrameric association and surface residues.
Main Results:
- A novel tetrameric association of mouse IP-10 was revealed, distinct from human IP-10 tetramers.
- The tetramer consists of two CXC chemokine dimers forming an elongated beta-sheet.
- Heparin- and receptor-binding residues were mapped, identifying two heparin-binding sites at dimer interfaces.
- The structure supports higher-order oligomer formation observed in vivo.
Conclusions:
- The determined structure provides a novel understanding of mouse IP-10 quaternary structure.
- The findings offer insights into IP-10's interaction with heparin and CXCR3.
- This structural information is valuable for designing targeted anti-inflammatory drugs.
Abstract:
Interferon-gamma-inducible protein (IP-10) belongs to the CXC class of chemokines and plays a significant role in the pathophysiology of various immune and inflammatory responses. It is also a potent angiostatic factor with antifibrotic properties. The biological activities of IP-10 are exerted by interactions with the G-protein-coupled receptor CXCR3 expressed on Th1 lymphocytes. IP-10 thus forms an attractive target for structure-based rational drug design of anti-inflammatory molecules. The crystal structure of mouse IP-10 has been determined and reveals a novel tetrameric association. In the tetramer, two conventional CXC chemokine dimers are associated through their N-terminal regions to form a 12-stranded elongated beta-sheet of approximately 90 A in length. This association differs significantly from the previously studied tetramers of human IP-10, platelet factor 4 and neutrophil-activating peptide-2. In addition, heparin- and receptor-binding residues were mapped on the surface of IP-10 tetramer. Two heparin-binding sites were observed on the surface and were present at the interface of each of the two beta-sheet dimers. The structure supports the formation of higher order oligomers of IP-10, as observed in recent in vivo studies with mouse IP-10, which will have functional relevance.
