Breaking down blood clots – understanding the structural basis of thrombin formation and function

Structural basis of thrombin formation and function

Blood clotting prevents uncontrolled bleeding; however, clots can prove lethal when they form inside arteries or veins. Heart attacks and stroke occur when a clot (thrombosis) forms in an artery leading to the heart or brain and prevents blood flow and oxygen reaching the organ. The root cause of thrombosis is inappropriate formation and activity of the protein, thrombin. Thrombin is the principal clotting factor and maintains the balance between bleeding and thrombosis. It is at the centre of a complex series of molecular events that result in a blood clot. Understanding how thrombin activity is regulated is critically important for understanding thrombosis. Thrombin clots blood by activating cells called platelets and chopping up a protein called fibrinogen to form fibrin. However, stable clots can only form if thrombin also stimulates a factor called prothrombin to produce more thrombin. It does this by activating another factor (factor V) and binding to other proteins that together assemble into a structure called the prothrombinase complex. The prothrombinase complex is very efficient at activating prothrombin. Dr James Huntington’s group at Cambridge University has been striving to understand what regulates thrombin activity and was the first to determine the unbound structure of thrombin. This grant will allow his team to work out how thrombin recognises factor V and identify in molecular detail, and structurally, how individual components of prothrombinase interact to initiate the burst of thrombin formation. He also hopes to determine the 3D structure of the prothrombinase complex. Studying the 3D structures of these complexes will enable the team to pinpoint sites where small molecule medicines can bind and potentially control prothrombinase activity. This programme will advance our understanding of blood clotting and may help scientists develop a novel class of medicines to prevent thrombosis.