Plasminogen (Plg) is the inactive zymogen form of the plasma chymotrypsin-like serine protease, plasmin (Plm). The latter protein directly cleaves fibrin clots and extracellular matrix components. In addition, it activates growth factors and proteases such as collagenases and complement C1r. The roles of Plg/Plm can be broadly divided into two main functional categories: Fibrinolysis, which maintains haemostasis and vascular patency, and cellular migration which facilitates tissue remodelling, wound healing, angiogenesis, inflammation, bacterial dissemination and metastasis. Therefore, both Plg and Plm are important potential drug targets for eliminating pathogenic clots in ischemic stroke and pulmonary embolism, and inhibiting bleeding as a result of surgical operations, traumatic injury or haemorrhagic disorder. Further, there is evidence suggesting that inhibiting Plm may be a useful strategy to reduce cancer metastasis.
We have determined the X-ray crystal structure of both glycoforms of Plg. However, we have only a limited understanding of how Plg is converted to Plm in its multitude of different functional settings and how to specifically dial down Plm activity when required. The focus of the study is to gain better understanding on the activation and inhibition of Plg and Plm. Specifically we perform structural and functional studies to characterize the interaction of Plm with small-molecule active site inhibitors and a number of Plg activators. Together, these studies will form the basis of new strategies to modulate Plg/Plm functions.