Crystal Structures of Urokinase-type Plasminogen Activator in Complex with 4-(Aminomethyl) Benzoic Acid and 4-(Aminometh

Urokinase-type plasminogen activator (uPA) is a trypsin-like serine protease and plays a key role in several biological processes, including tissue remodeling, cell migration, and matrix degradation. The inhibitors of uPA have been shown to prevent the spread of metastasis and tumor growth, and accordingly uPA is widely recognized as a target for the treatment of cancer. In this work, we report the crystal structures of the complexes of uPA with its inhibitors: 4-(aminomethyl)-benzoic acid (AMBA) and 4-(aminomethyl-phenyl)-methanol (AMPM), both at a resolution of 2.35 A. The inhibitory constants of these two inhibitors were measured by a chromogenic competitive assay, and it was found that AMBA is a better inhibitor for uPA (Ki = 2.68 mM) than AMPM (Ki = 13.99 mM). The structural study shows that the binding mode of inhibitor AMBA on uPA is similar to that of AMPM on uPA, both docked into the active site S1 pocket of uPA. Structural details of these complexes are provided to explain the difference of inhibitory constants.

作 者： JIANG Long-Guang ZHAO Geng-Xiang BIAN Chuan-Bing YUAN Cai HUANG Zi-Xiang HUANG Ming-Dong   作者單位： JIANG Long-Guang,ZHAO Geng-Xiang(State Key Laboratory of Structural Chemistry,Fujian Institute of Research on the Structure of Matter,The Chinese Academy of Sciences,Fuzhou,Fujian 350002,China;Graduate School of the Chinese Academy of Sciences,Beijing 100039,China)

BIAN Chuan-Bing,YUAN Cai,HUANG Zi-Xiang,HUANG Ming-Dong(State Key Laboratory of Structural Chemistry,Fujian Institute of Research on the Structure of Matter,The Chinese Academy of Sciences,Fuzhou,Fujian 350002,China) 

刊 名： 結構化學  ISTIC SCI PKU 英文刊名： CHINESE JOURNAL OF STRUCTURAL CHEMISTRY  年，卷(期)： 2009 28(2)  分類號： O6  關鍵詞： uroktnase-type plasminogen activator   4-(aminomethyl)benzoic acid   (4-aminomethyl-phenyl)-methanol   enzyme inhibition assays   contact area  

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