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| {{STRUCTURE_1xdd| PDB=1xdd | SCENE= }} | | {{STRUCTURE_1xdd| PDB=1xdd | SCENE= }} |
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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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| ==Overview==
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| 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. | | The line below this paragraph, {{ABSTRACT_PUBMED_15304496}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 15304496 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_15304496}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: I-domain]] | | [[Category: I-domain]] |
| [[Category: Rossman fold]] | | [[Category: Rossman fold]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 14:53:12 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 13:27:16 2008'' |
