1xdd: Difference between revisions
New page: left|200px<br /> <applet load="1xdd" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xdd, resolution 2.20Å" /> '''X-ray structure of ... |
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[[Image:1xdd.gif|left|200px]]<br /> | [[Image:1xdd.gif|left|200px]]<br /><applet load="1xdd" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1xdd, resolution 2.20Å" /> | caption="1xdd, resolution 2.20Å" /> | ||
'''X-ray structure of LFA-1 I-domain in complex with LFA703 at 2.2A resolution'''<br /> | '''X-ray structure of LFA-1 I-domain in complex with LFA703 at 2.2A resolution'''<br /> | ||
==Overview== | ==Overview== | ||
The integrin lymphocyte function-associated antigen-1 (LFA-1) | 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== | ==About this Structure== | ||
1XDD is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG and AAY as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 1XDD is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=AAY:'>AAY</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XDD OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: rossman fold]] | [[Category: rossman fold]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:53:35 2008'' | ||
Revision as of 16:53, 21 February 2008
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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 and 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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