Author: Kallen J. Welzenbach K. Ramage P. Geyl D. Kriwacki R. Legge G. Cottens S. Weitz-Schmidt G. Hommel U.
Publisher: Academic Press
ISSN: 0022-2836
Source: Journal of Molecular Biology, Vol.292, Iss.1, 1999-09, pp. : 1-9
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Abstract
The lymphocyte function-associated antigen (LFA-1) belongs to the family of &bgr;2-integrins and plays an important role in T-cell activation and leukocyte migration to sites of inflammation. We report here that lovastatin, a drug clinically used for lowering cholesterol levels, inhibits the interaction of human LFA-1 with its counter-receptor intercellular adhesion molecule-1. Using nuclear magnetic resonance spectroscopy and X-ray crystallography we show that the inhibitor binds to a highly conserved domain of the LFA-1 -chain called the I-domain. The first three-dimensional structure of an integrin inhibitor bound to its receptor reveals atomic details for a hitherto unknown mode of LFA-1 inhibition. It also sheds light into possible mechanisms of LFA-1 mediated signalling and will support the design of novel anti-adhesive and immunosuppressive drugs.