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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''' | '''X-ray structure of LFA-1 I-domain in complex with LFA703 at 2.2A resolution''' | ||
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[[Category: Weitz-Schmidt, G.]] | [[Category: Weitz-Schmidt, G.]] | ||
[[Category: Welzenbach, K.]] | [[Category: Welzenbach, K.]] | ||
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Revision as of 11:53, 3 May 2008
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 Sat May 3 14:53:12 2008
