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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

Backbone tracing of the oligomeric structures formed in mouse and human IP-10, platelet factor 4 and neutrophil-activating peptide-2. Four chains are shown in each structure, in which a typical chemokine dimer is formed between the green and magenta chains and the blue and grey chains, respectively. Note the different association of dimers in each structure. This figure was drawn using the program SwissPDBViewer (Guex & Peitsch, 1997 ▶).
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fig5: Backbone tracing of the oligomeric structures formed in mouse and human IP-10, platelet factor 4 and neutrophil-activating peptide-2. Four chains are shown in each structure, in which a typical chemokine dimer is formed between the green and magenta chains and the blue and grey chains, respectively. Note the different association of dimers in each structure. This figure was drawn using the program SwissPDBViewer (Guex & Peitsch, 1997 ▶).

Mentions: The mouse IP-10 structure differs significantly in its tetrameric association from human IP-10 structures. The human IP-­10 tetramer in the monoclinic space group (M form) is formed by the association of two pseudosymmetrical dimers such that the two six-stranded β-sheets face each other while the C-terminal helices are present on the exterior. This arrangement of subunits is similar to the tetramers of the CXC chemokines PF4 (Zhang et al., 1994 ▶) and NAP-2 (Malkowski et al., 1995 ▶) (Fig. 5 ▶). In the tetragonal (T form) and hexagonal (H form) space groups, the human IP-10 dimers associate with the symmetry-related dimers through their β3 strands to form a 12-stranded antiparallel β-sheet structure that has a sharp kink in the middle which gives an open barrel-shaped structure to the complex. However, in the H-form tetramer, the dimers also form N-terminal asymmetric interactions, thus bringing the chains closer (Swaminathan et al., 2003 ▶). The crystal packing of the human IP-10 structures in all three space groups show different arrangements of molecules compared with the mouse IP-10 structure. In contrast to the mouse IP-10 structure, which has an elongated cylindrical shape, all these tetramers form globular-shaped structures (Fig. 5 ▶).


Structure of mouse IP-10, a chemokine.

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

Backbone tracing of the oligomeric structures formed in mouse and human IP-10, platelet factor 4 and neutrophil-activating peptide-2. Four chains are shown in each structure, in which a typical chemokine dimer is formed between the green and magenta chains and the blue and grey chains, respectively. Note the different association of dimers in each structure. This figure was drawn using the program SwissPDBViewer (Guex & Peitsch, 1997 ▶).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Backbone tracing of the oligomeric structures formed in mouse and human IP-10, platelet factor 4 and neutrophil-activating peptide-2. Four chains are shown in each structure, in which a typical chemokine dimer is formed between the green and magenta chains and the blue and grey chains, respectively. Note the different association of dimers in each structure. This figure was drawn using the program SwissPDBViewer (Guex & Peitsch, 1997 ▶).
Mentions: The mouse IP-10 structure differs significantly in its tetrameric association from human IP-10 structures. The human IP-­10 tetramer in the monoclinic space group (M form) is formed by the association of two pseudosymmetrical dimers such that the two six-stranded β-sheets face each other while the C-terminal helices are present on the exterior. This arrangement of subunits is similar to the tetramers of the CXC chemokines PF4 (Zhang et al., 1994 ▶) and NAP-2 (Malkowski et al., 1995 ▶) (Fig. 5 ▶). In the tetragonal (T form) and hexagonal (H form) space groups, the human IP-10 dimers associate with the symmetry-related dimers through their β3 strands to form a 12-stranded antiparallel β-sheet structure that has a sharp kink in the middle which gives an open barrel-shaped structure to the complex. However, in the H-form tetramer, the dimers also form N-terminal asymmetric interactions, thus bringing the chains closer (Swaminathan et al., 2003 ▶). The crystal packing of the human IP-10 structures in all three space groups show different arrangements of molecules compared with the mouse IP-10 structure. In contrast to the mouse IP-10 structure, which has an elongated cylindrical shape, all these tetramers form globular-shaped structures (Fig. 5 ▶).

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