Poster Presentation 9th General Meeting of the International Proteolysis Society 2015

The x-ray crystal structure of microplasmin with a small-molecular active site inhibitor PSI-112 (#171)

Guojie Wu 1 , Koushi Hidaka 2 , Davadharshini Jeevarajah , Yuko Tsuda 3 , James C Whisstock 1 4 , Ruby H.P. Law 1
  1. ARC Centre of Excellence in Advanced Molecular Imaging, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  2. Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto, Japan
  3. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan
  4. ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Melbourne, VIC 3800, Australia

    Plasmin (Plm) is the active form of the zymogen plasminogen (Plg), a serine protease which plays a key role in the fibrinolytic system and several other physiological activities. Physiologically, Plg/Plm activity is regulated by specific inhibitors and activators, making it an attractive therapeutic target for both traumatic bleeding and thrombotic diseases. Here we report the first crystal structure of microplasmin (the catalytic domain of Plm) in complex with a small-molecular active site inhibitor PSI-112 which is highly specific for Plm with IC50 of 0.22 µM. The crystal structure has been determined to 1.62Å, and the inhibitor binds to the substrate binding pocket with extensive additional subsite interactions. This structure may be helpful in developing a more Plm specific inhibitor as a new anti-fibrinolytic agent used to reduce bleeding complications in cardiac surgery or liver transplantation.