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Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain.
Kallen, J; Welzenbach, K; Ramage, P; Geyl, D; Kriwacki, R; Legge, G; Cottens, S; Weitz-Schmidt, G; Hommel, U.
Afiliação
  • Kallen J; Preclinical Research, NOVARTIS PHARMA AG, Basel, CH 4002, Switzerland.
J Mol Biol ; 292(1): 1-9, 1999 Sep 10.
Article em En | MEDLINE | ID: mdl-10493852
The lymphocyte function-associated antigen (LFA-1) belongs to the family of beta2-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 alpha-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.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Lovastatina / Antígeno-1 Associado à Função Linfocitária / Antígenos CD11 Limite: Humans Idioma: En Revista: J Mol Biol Ano de publicação: 1999 Tipo de documento: Article País de afiliação: Suíça País de publicação: Holanda
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Lovastatina / Antígeno-1 Associado à Função Linfocitária / Antígenos CD11 Limite: Humans Idioma: En Revista: J Mol Biol Ano de publicação: 1999 Tipo de documento: Article País de afiliação: Suíça País de publicação: Holanda