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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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Related in: MedlinePlus

Stereo representation of the hydrogen bonds formed at the A–B interface. Residues from molecule A are shown in blue and those from molecule B in pink.
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fig4: Stereo representation of the hydrogen bonds formed at the A–B interface. Residues from molecule A are shown in blue and those from molecule B in pink.

Mentions: In addition to the A–D and B–C dimers, another dimer is formed between molecules A and B in the mouse IP-10 structure. This results in a distinct tetrameric assembly that is formed by the association of two pseudosymmetrical dimers: A–D and B–C (Fig. 3 ▶). The tetramer has an elongated structure with approximate dimensions of 90 × 40 Å2. Intermolecular contacts in the tetramer are through molecules A and B. The two molecules associate through their N-terminal loops in an antiparallel fashion such that their α-helices lie on one face of the β-strands, while the interacting N-terminal loops are on the back of the strands. The rotation axis parallel to the β-sheets and dissecting the A–B dimer relates chains A and B with a rotation angle of 179.1°, as calculated by LSQMAN (Kleywegt & Jones, 1994 ▶). This is a novel association in which the tetramer consists of two six-stranded antiparallel β-sheets, with an antiparallel sheet formed by the N-­terminal regions between the two six-stranded β-­sheets and all four helices lying on one face of the β-sheet (Fig. 4 ▶). This type of association differs significantly from many of the chemokine oligomeric structures studied to date. Intermolecular association through N-terminal regions has been observed previously in CC chemokines such as MIP-1β (Lodi et al., 1994 ▶) and RANTES (Shaw et al., 2004 ▶). However, these dimeric structures differ considerably from the A–B dimer in the present structure. In these CC chemokines, two monomers associate together such that their three-stranded β-sheets face each other with a short β-sheet formed by the interacting N-­terminal regions in the centre. The C-terminal helix of each of the monomer lies on the exterior face of the β-sheet.


Structure of mouse IP-10, a chemokine.

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

Stereo representation of the hydrogen bonds formed at the A–B interface. Residues from molecule A are shown in blue and those from molecule B in pink.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Stereo representation of the hydrogen bonds formed at the A–B interface. Residues from molecule A are shown in blue and those from molecule B in pink.
Mentions: In addition to the A–D and B–C dimers, another dimer is formed between molecules A and B in the mouse IP-10 structure. This results in a distinct tetrameric assembly that is formed by the association of two pseudosymmetrical dimers: A–D and B–C (Fig. 3 ▶). The tetramer has an elongated structure with approximate dimensions of 90 × 40 Å2. Intermolecular contacts in the tetramer are through molecules A and B. The two molecules associate through their N-terminal loops in an antiparallel fashion such that their α-helices lie on one face of the β-strands, while the interacting N-terminal loops are on the back of the strands. The rotation axis parallel to the β-sheets and dissecting the A–B dimer relates chains A and B with a rotation angle of 179.1°, as calculated by LSQMAN (Kleywegt & Jones, 1994 ▶). This is a novel association in which the tetramer consists of two six-stranded antiparallel β-sheets, with an antiparallel sheet formed by the N-­terminal regions between the two six-stranded β-­sheets and all four helices lying on one face of the β-sheet (Fig. 4 ▶). This type of association differs significantly from many of the chemokine oligomeric structures studied to date. Intermolecular association through N-terminal regions has been observed previously in CC chemokines such as MIP-1β (Lodi et al., 1994 ▶) and RANTES (Shaw et al., 2004 ▶). However, these dimeric structures differ considerably from the A–B dimer in the present structure. In these CC chemokines, two monomers associate together such that their three-stranded β-sheets face each other with a short β-sheet formed by the interacting N-­terminal regions in the centre. The C-terminal helix of each of the monomer lies on the exterior face of the β-sheet.

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