Crystals of the urokinase type plasminogen activator variant βc-uPA in complex with small molecule inhibitors open the way towards structure-based drug design

被引:74
作者
Zeslawska, E
Schweinitz, A
Karcher, A
Sondermann, P
Sperl, S
Stürzebecher, J
Jacob, U
机构
[1] Max Planck Inst Biochem, Abt Strukturforsch, D-82152 Martinsried, Germany
[2] Univ Jena, Inst Biochem & Biophys, D-07743 Jena, Germany
关键词
urokinase; amiloride; crystal structure; crystal engineering; drug design;
D O I
10.1006/jmbi.2000.3966
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Urokinase is a serine protease involved in cancer growth and metastasis. Here we present the first urokinase crystal structure in complex with reversible inhibitors at 2.1 and 2.6 Angstrom resolution. These inhibitor complex structures have been obtained from crystals of engineered urokinase type plasminogen activator designed to obtain a crystal form open for inhibitor soaking. The mutant C122S loses its flexible A-chain upon activation cleavage and crystallises in the presence of benzamidine, which was later displaced by the desired inhibitor. This new soakable crystal form turned out to be of great value in the process of structure-based drug design. The evaluated binding mode of amiloride, and UKI-1D revealed a new subsite of the primary specificity pocket of urokinase that will be employed in the future ligand optimisation process. (C) 2000 Academic Press.
引用
收藏
页码:465 / 475
页数:11
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