Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain
Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain
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DOI：
10.1006/jmbi.1999.3047
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发表时间：
1999-09-10
影响因子：
5.6
通讯作者：
Hommel, U
中科院分区：
文献类型：
--
作者：
Kallen, J;Welzenbach, K;Hommel, U
淋巴细胞功能相关抗原（LFA-1）属于β（2）-整联蛋白家族，在T细胞活化和白细胞向炎症部位迁移中起重要作用。我们在这里报告，洛伐他汀，临床上用于降低胆固醇水平的药物，抑制人LFA-1与其反受体细胞间粘附分子-1的相互作用。使用核磁共振光谱和X-射线晶体学，我们表明，抑制剂结合到一个高度保守的结构域的LFA-1 α链称为I-域。与其受体结合的整合素抑制剂的第一个三维结构揭示了迄今未知的LFA-1抑制模式的原子细节。它还揭示了LFA-1介导的信号传导的可能机制，并将支持新型抗粘附和免疫抑制药物的设计。(C)北京：科学出版社.
The lymphocyte function-associated antigen (LFA-1) belongs to the family of beta(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 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. (C) 1999 Academic Press.