1xdd
From Proteopedia
| Line 4: | Line 4: | ||
|PDB= 1xdd |SIZE=350|CAPTION= <scene name='initialview01'>1xdd</scene>, resolution 2.20Å | |PDB= 1xdd |SIZE=350|CAPTION= <scene name='initialview01'>1xdd</scene>, resolution 2.20Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= | + | |LIGAND= <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>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1xdg|1XDG]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1xdd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xdd OCA], [http://www.ebi.ac.uk/pdbsum/1xdd PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1xdd RCSB]</span> | ||
}} | }} | ||
| Line 26: | Line 29: | ||
[[Category: Weitz-Schmidt, G.]] | [[Category: Weitz-Schmidt, G.]] | ||
[[Category: Welzenbach, K.]] | [[Category: Welzenbach, K.]] | ||
| - | [[Category: AAY]] | ||
| - | [[Category: MG]] | ||
[[Category: i-domain]] | [[Category: i-domain]] | ||
[[Category: rossman fold]] | [[Category: rossman fold]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:48:03 2008'' |
Revision as of 21:48, 30 March 2008
| |||||||
| , resolution 2.20Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Related: | 1XDG
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| 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 Mon Mar 31 00:48:03 2008
