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Structure of mouse IP-10, a chemokine.

Jabeen T, Leonard P, Jamaluddin H, Acharya KR - Acta Crystallogr. D Biol. Crystallogr. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, England.

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.

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Stereoview of the intermolecular interactions at the B–C interface. Residues from molecules B and C are shown in pink and green, respectively. Similar interactions between the β1 strands were observed at the A–D interface.
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fig2: Stereoview of the intermolecular interactions at the B–C interface. Residues from molecules B and C are shown in pink and green, respectively. Similar interactions between the β1 strands were observed at the A–D interface.

Mentions: The dimers (A–D and B–C) are primarily stabilized by reciprocal interactions between opposing β1 strands. The main-chain hydrogen bonding at the interface is limited to reciprocal interactions between residues Leu27 and Ile29 (thus accounting for four hydrogen bonds) owing to the presence of Pro31, which disrupts the β-structure. Similar interactions were observed in human IP-10 dimers owing to the conserved Pro31. However, in other CXC chemokines this position is occupied by residues other than Pro and hence four residues are involved in main-chain reciprocal interactions compared with two in the IP-10 structures. Additional interactions at the interface are contributed by salt bridges between residues Lys26 and Glu28 of the β1 strands from both the molecules in addition to extensive van der Waals contacts. The involvement of the C-terminal helices in the intermolecular interactions is limited owing to their short lengths and consists of two hydrogen bonds between residues Lys62 Nζ and Lys66 Nζ of molecule B with Phe68 O and Ala67 O of molecule C, respectively. The ionic interactions at the C-terminal regions are absent in molecules A and D and only van der Waals contacts are made (Table 2 ▶, Fig. 2 ▶). The interfaces between A and D and between B and C bury 1280 and 1170 Å2 of solvent-accessible surface area, respectively, which is comparable to the buried surface areas of other CXC chemokine dimers.


Structure of mouse IP-10, a chemokine.

Jabeen T, Leonard P, Jamaluddin H, Acharya KR - Acta Crystallogr. D Biol. Crystallogr. (2008)

Stereoview of the intermolecular interactions at the B–C interface. Residues from molecules B and C are shown in pink and green, respectively. Similar interactions between the β1 strands were observed at the A–D interface.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2665906&req=5

fig2: Stereoview of the intermolecular interactions at the B–C interface. Residues from molecules B and C are shown in pink and green, respectively. Similar interactions between the β1 strands were observed at the A–D interface.
Mentions: The dimers (A–D and B–C) are primarily stabilized by reciprocal interactions between opposing β1 strands. The main-chain hydrogen bonding at the interface is limited to reciprocal interactions between residues Leu27 and Ile29 (thus accounting for four hydrogen bonds) owing to the presence of Pro31, which disrupts the β-structure. Similar interactions were observed in human IP-10 dimers owing to the conserved Pro31. However, in other CXC chemokines this position is occupied by residues other than Pro and hence four residues are involved in main-chain reciprocal interactions compared with two in the IP-10 structures. Additional interactions at the interface are contributed by salt bridges between residues Lys26 and Glu28 of the β1 strands from both the molecules in addition to extensive van der Waals contacts. The involvement of the C-terminal helices in the intermolecular interactions is limited owing to their short lengths and consists of two hydrogen bonds between residues Lys62 Nζ and Lys66 Nζ of molecule B with Phe68 O and Ala67 O of molecule C, respectively. The ionic interactions at the C-terminal regions are absent in molecules A and D and only van der Waals contacts are made (Table 2 ▶, Fig. 2 ▶). The interfaces between A and D and between B and C bury 1280 and 1170 Å2 of solvent-accessible surface area, respectively, which is comparable to the buried surface areas of other CXC chemokine dimers.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, England.

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.

Show MeSH
Related in: MedlinePlus