1xdg: Difference between revisions
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[[Image:1xdg.gif|left|200px]] | [[Image:1xdg.gif|left|200px]] | ||
'''X-ray structure of LFA-1 I-domain in complex with LFA878 at 2.1A resolution''' | {{Structure | ||
|PDB= 1xdg |SIZE=350|CAPTION= <scene name='initialview01'>1xdg</scene>, resolution 2.10Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene> and <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> | |||
|ACTIVITY= | |||
|GENE= | |||
}} | |||
'''X-ray structure of LFA-1 I-domain in complex with LFA878 at 2.1A resolution''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1XDG is a [ | 1XDG 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=1XDG 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 15:08:20 2008'' | ||
Revision as of 16:08, 20 March 2008
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| , resolution 2.10Å | |||||||
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| 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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