Plasminogen is the inactive, precursor form of the fibrinolytic protease plasmin. The enzyme plays a major role in dissolving blood clots as well as a host of secondary functions and is a major target for the design of novel anti-clotting therapeutic drugs. We have recently determined the structure of human plasminogen by x-ray crystallography ¹ . The protein is composed of five discrete structured units (domains) that are covalently joined by unstructured linkers along the polypeptide chain. A model based on the x-ray diffraction data reveals molecular detail of how the domains pack tightly together to mask the active site of the protease domain in the inactive protein.

Upon activation the inter-domain contacts are weakened and the protein opens into an extended and flexible conformation that is less tractable to study by protein crystallography. Although there are several, well-characterized activators of plasminogen, the molecular mechanism of activation is poorly understood. We have used SAXS to characterise human plasminogen in its active, extended conformation. In addition we have found that SAXS is a useful assay for studying the kinetics of activation and this approach has led to some useful insights into plasminogen function.