Structure of mouse IP-10, a chemokine.
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.
Jabeen
Talat
T
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, England.
Leonard
Philip
P
Jamaluddin
Haryati
H
Acharya
K Ravi
KR
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D054357:Chemokine CXCL10 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D006025:Glycosaminoglycans / Q000378:metabolism; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D054367:Receptors, CXCR3 / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D006025:Glycosaminoglycans; D054367:Receptors, CXCR3; D011994:Recombinant Proteins