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| - | [[Image:2nwg.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2nwg| PDB=2nwg | SCENE= }} | | {{STRUCTURE_2nwg| PDB=2nwg | SCENE= }} |
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| - | '''Structure of CXCL12:heparin disaccharide complex'''
| + | ===Structure of CXCL12:heparin disaccharide complex=== |
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| - | ==Overview==
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| - | CXCL12 (SDF-1alpha) and CXCR4 are critical for embryonic development and cellular migration in adults. These proteins are involved in HIV-1 infection, cancer metastasis, and WHIM disease. Sequestration and presentation of CXCL12 to CXCR4 by glycosaminoglycans (GAGs) is proposed to be important for receptor activation. Mutagenesis has identified CXCL12 residues that bind to heparin. However, the molecular details of this interaction have not yet been determined. Here we demonstrate that soluble heparin and heparan sulfate negatively affect CXCL12-mediated in vitro chemotaxis. We also show that a cluster of basic residues in the dimer interface is required for chemotaxis and is a target for inhibition by heparin. We present structural evidence for binding of an unsaturated heparin disaccharide to CXCL12 attained through solution NMR spectroscopy and x-ray crystallography. Increasing concentrations of the disaccharide altered the two-dimensional (1)H-(15)N-HSQC spectra of CXCL12, which identified two clusters of residues. One cluster corresponds to beta-strands in the dimer interface. The second includes the amino-terminal loop and the alpha-helix. In the x-ray structure two unsaturated disaccharides are present. One is in the dimer interface with direct contacts between residues His(25), Lys(27), and Arg(41) of CXCL12 and the heparin disaccharide. The second disaccharide contacts Ala(20), Arg(21), Asn(30), and Lys(64). This is the first x-ray structure of a CXC class chemokine in complex with glycosaminoglycans. Based on the observation of two heparin binding sites, we propose a mechanism in which GAGs bind around CXCL12 dimers as they sequester and present CXCL12 to CXCR4.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_17264079}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 17264079 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_17264079}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Murphy, J W.]] | | [[Category: Murphy, J W.]] |
| | [[Category: Protein-glycosaminoglycan complex]] | | [[Category: Protein-glycosaminoglycan complex]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 09:59:43 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 00:40:11 2008'' |
Revision as of 21:40, 28 July 2008
Template:STRUCTURE 2nwg
Structure of CXCL12:heparin disaccharide complex
Template:ABSTRACT PUBMED 17264079
About this Structure
2NWG is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural and functional basis of CXCL12 (stromal cell-derived factor-1 alpha) binding to heparin., Murphy JW, Cho Y, Sachpatzidis A, Fan C, Hodsdon ME, Lolis E, J Biol Chem. 2007 Mar 30;282(13):10018-27. Epub 2007 Jan 29. PMID:17264079
Page seeded by OCA on Tue Jul 29 00:40:11 2008
