1xdd
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X-ray structure of LFA-1 I-domain in complex with LFA703 at 2.2A 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
1XDD is a Single protein structure of sequence from Homo sapiens with MG and AAY as ligands. 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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