1XDG

X-ray structure of LFA-1 I-domain in complex with LFA878 at 2.1A resolution

Summary for 1XDG

• Entry DOI: 10.2210/pdb1xdg/pdb
• Related: 1XDD
• Descriptor: Integrin alpha-L, MAGNESIUM ION, (1S,3R,8AS)-8-(2-{(4S,6S)-3-(4-HYDROXY-3-METHOXYBENZYL)-4-[2-(METHYLAMINO)-2-OXOETHYL]-2-OXO-1,3-OXAZINAN-6-YL}ETHYL)-3 ,7-DIMETHYL-1,2,3,7,8,8A-HEXAHYDRONAPHTHALEN-1-YL (2R)-2-METHYLBUTANOATE, ... (4 entities in total)
• Functional Keywords: rossman-fold, i-domain, immune system
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P20701
• Total number of polymer chains: 2
• Total formula weight: 44093.24

Authors

Weitz-Schmidt, G.,Welzenbach, K.,Dawson, J.,Kallen, J. (deposition date: 2004-09-06, release date: 2004-09-21, Last modification date: 2023-10-25)

Primary citation

Weitz-Schmidt, G.,Welzenbach, K.,Dawson, J.,Kallen, J.
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
J.Biol.Chem., 279:46764-46771, 2004

PubMed Abstract: 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.

PubMed: 15304496
DOI: 10.1074/jbc.M407951200

Experimental method

X-RAY DIFFRACTION (2.1 Å)