Research

Molecular Recognition in Haemostasis

Blood coagulation (haemostasis) is a complex process under tight regulatory control. Dysregulatoin leads to bleeding when the clotting response is insufficiently rapid and robust, and to thrombosis when coagulation is not limited. This ‘haemostatic balance’ is critical for human health, and understanding the regulatory mechanisms is crucial for the diagnosis, prevention and treatment of diseases such as haemophilia, deep vein thrombosis, pulmonary embolism, heart attack, and stroke.
My lab studies the molecular events which maintain the haemostatic balance mainly by determining crystallographic structures of individual coagulation factors and of the multi-protein complexes they form. We have several projects running concurrently in the lab.
The serpin project studies how the inhibitory activity of serpins is stimulated by heparin-like glycosaminoglycans. We have succeeded in defining the mode of action of therapeutic heparin by solving the structures of antithrombin and heparin cofactor II in recognition complexes with target haemostatic proteases, and have recently solved a similar structure of protein C inhibitor demonstrating how it carries out its procoagulant function.
Another project in the lab focuses on determining the molecular basis of thrombin function. This has traditionally involved crystallographic studies of thrombin complexed to substrates, cofactors and inhibitors. We now have a productive NMR-based thrombin effort which promises to unveil the functional relevance of thrombin allostery and to map interactions with its molecular partners. The events which lead to thrombin formation are also studied. We are crystallising individual members of the haemostatic network of proteins and the complexes they form. In the long term, our efforts will define the principal molecular recognition events which govern haemostasis