1xdg: Difference between revisions
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|PDB= 1xdg |SIZE=350|CAPTION= <scene name='initialview01'>1xdg</scene>, resolution 2.10Å | |PDB= 1xdg |SIZE=350|CAPTION= <scene name='initialview01'>1xdg</scene>, resolution 2.10Å | ||
|SITE= | |SITE= | ||
|LIGAND= | |LIGAND= <scene name='pdbligand=AB8:(1S,3R,8AS)-8-(2-{(4S,6S)-3-(4-HYDROXY-3-METHOXYBENZYL)-4-[2-(METHYLAMINO)-2-OXOETHYL]-2-OXO-1,3-OXAZINAN-6-YL}ETHYL)-3,7-DIMETHYL-1,2,3,7,8,8A-HEXAHYDRONAPHTHALEN-1-YL+(2R)-2-METHYLBUTANOATE'>AB8</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene> | ||
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY=[[1xdd|1XDD]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1xdg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xdg OCA], [http://www.ebi.ac.uk/pdbsum/1xdg PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1xdg RCSB]</span> | |||
}} | }} | ||
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[[Category: Weitz-Schmidt, G.]] | [[Category: Weitz-Schmidt, G.]] | ||
[[Category: Welzenbach, K.]] | [[Category: Welzenbach, K.]] | ||
[[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 00:48:06 2008'' | ||
Revision as of 00:48, 31 March 2008
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| , resolution 2.10Å | |||||||
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| Ligands: | , | ||||||
| Related: | 1XDD
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
X-ray structure of LFA-1 I-domain in complex with LFA878 at 2.1A resolution
OverviewOverview
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 StructureAbout this Structure
1XDG is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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
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