1xdd
From Proteopedia
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| - | [[Image:1xdd.gif|left|200px]] | + | [[Image:1xdd.gif|left|200px]] |
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| - | '''X-ray structure of LFA-1 I-domain in complex with LFA703 at 2.2A resolution''' | + | {{Structure |
| + | |PDB= 1xdd |SIZE=350|CAPTION= <scene name='initialview01'>1xdd</scene>, resolution 2.20Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene> and <scene name='pdbligand=AAY:8-[2-((2S)-4-HYDROXY-1-{[5-(HYDROXYMETHYL)-6-METHOXY-2-NAPHTHYL]METHYL}-6-OXOPIPERIDIN-2-YL)ETHYL]-3,7-DIMETHYL-1,2,3,7,8,8A-HEXAHYDRONAPHTHALEN-1-YL 2-METHYLBUTANOATE'>AAY</scene> | ||
| + | |ACTIVITY= | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''X-ray structure of LFA-1 I-domain in complex with LFA703 at 2.2A resolution''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1XDD is a [ | + | 1XDD is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XDD OCA]. |
==Reference== | ==Reference== | ||
| - | Improved lymphocyte function-associated antigen-1 (LFA-1) inhibition by statin derivatives: molecular basis determined by x-ray analysis and monitoring of LFA-1 conformational changes in vitro and ex vivo., Weitz-Schmidt G, Welzenbach K, Dawson J, Kallen J, J Biol Chem. 2004 Nov 5;279(45):46764-71. Epub 2004 Aug 10. PMID:[http:// | + | Improved lymphocyte function-associated antigen-1 (LFA-1) inhibition by statin derivatives: molecular basis determined by x-ray analysis and monitoring of LFA-1 conformational changes in vitro and ex vivo., Weitz-Schmidt G, Welzenbach K, Dawson J, Kallen J, J Biol Chem. 2004 Nov 5;279(45):46764-71. Epub 2004 Aug 10. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15304496 15304496] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: rossman fold]] | [[Category: rossman fold]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 15:08:24 2008'' |
Revision as of 13:08, 20 March 2008
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| , resolution 2.20Å | |||||||
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| Ligands: | and | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
X-ray structure of LFA-1 I-domain in complex with LFA703 at 2.2A resolution
Overview
The integrin lymphocyte function-associated antigen-1 (LFA-1) (alphaLbeta2; CD11a/CD18) plays an important role in leukocyte migration and T cell activation. LFA-1 is inhibited by the cholesterol-lowering drug lovastatin, which binds to an allosteric site of the alphaL I domain termed the lovastatin site (L-site). Here we report for the first time the x-ray structures of the LFA-1 I domain complexed with derivatives of lovastatin optimized for LFA-1 inhibition. This analysis identified two new subpockets within the L-site occupied by chemical groups of the statin derivatives but not by lovastatin itself. Occupancy of these L-site subpockets led to distinct conformational changes in LFA-1, which were detectable by an epitope-monitoring assay. We utilized this assay to demonstrate improved LFA-1 inhibition in human blood in vitro and in blood samples from treated animals ex vivo. Moreover, we demonstrate that the novel lovastatin-derived LFA-1 inhibitor LFA878 exhibits potent anti-inflammatory effects in carrageenan-induced rat paw edema. In summary, the findings reported here extend the understanding of LFA-1 inhibition at the molecular level, allow for the identification and design of LFA-1 inhibitors of further enhanced potency, and support the expectation that LFA-1 inhibitors binding to the L-site will be of therapeutic value in treating inflammatory diseases.
About this Structure
1XDD is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Improved lymphocyte function-associated antigen-1 (LFA-1) inhibition by statin derivatives: molecular basis determined by x-ray analysis and monitoring of LFA-1 conformational changes in vitro and ex vivo., Weitz-Schmidt G, Welzenbach K, Dawson J, Kallen J, J Biol Chem. 2004 Nov 5;279(45):46764-71. Epub 2004 Aug 10. PMID:15304496
Page seeded by OCA on Thu Mar 20 15:08:24 2008
Categories: Homo sapiens | Single protein | Dawson, J. | Kallen, J. | Weitz-Schmidt, G. | Welzenbach, K. | AAY | MG | I-domain | Rossman fold
