1xdd

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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'''
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===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.
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(as it appears on PubMed at http://www.pubmed.gov), where 15304496 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15304496}}
==About this Structure==
==About this Structure==
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[[Category: I-domain]]
[[Category: I-domain]]
[[Category: Rossman fold]]
[[Category: Rossman fold]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 14:53:12 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 13:27:16 2008''

Revision as of 10:27, 27 July 2008

Image:1xdd.png

Template:STRUCTURE 1xdd

X-ray structure of LFA-1 I-domain in complex with LFA703 at 2.2A resolution

Template:ABSTRACT PUBMED 15304496

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

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