Basic and translational research into thrombosis, haemophilia and antitrypsin deficiency
Haemostasis (blood coagulation) is a complex process under tight regulatory control, with dysregulation resulting in bleeding or thrombosis. The main focus of my lab is to develop a structural understanding of these regulatory mechanisms, with the expectation that such information will help improve therapies for the prevention and treatment of diseases such as haemophilia, deep vein thrombosis, pulmonary embolism, heart attack and stroke. Our basic research into haemostasis centres on the two molecular engines of clot formation: the intrinsic Xase complex and the prothrombinase complex. These complexes are homologous and consist of a protease component and a cofactor. The Xase complex is composed of factor (f) IXa and fVIIIa, and as the name suggests, its function is to convert the zymogen fX to the active protease fXa. The prothrombinase complex produces thrombin from prothrombin, and is composed of fXa and fVa. Haemophilia is caused by deficiencies in either fIX or fVIII, and thrombosis is caused by excessive thrombin formation. We have recently solved the crystal structure of the prothrombinase complex from the venom of the Australian brown snake Pseudonaja textilis, and work is on-going to determine how it relates to human prothrombinase and the intrinsic Xase complex. In addition to this basic research, we have active translational projects in the field of thrombosis and haemophilia. In collaboration with Trevor Baglin from Addenbrooke’s Trust we have invented a first-in-class antithrombotic agent (ichorcumab) that has attracted an $11M series A investment (XO1 Ltd), and promises to dissociate efficacy from bleeding risk. In addition, we are working on strategies to treat and prevent haemophilia by attenuating the anticoagulant protein C system.
Another major project in the lab is to determine the molecular basis of serpin polymerisation. We have revolutionised the field with crystal structures of intact serpin dimers and trimers that revealed unexpected and extensive domain swapping. Importantly, we have compelling structural data on how the common Z-mutation results in the misfolding and polymerisation of α1-antitrypsin, and are pursuing strategies that will rescue folding and ameliorate lung and liver manifestations of antitrypsin deficiency.
Lechtenberg, B.C., Murray-Rust, T.A., Johnson, D.J., Adams, T.E., Krishnaswamy, S., Camire, R.M. and Huntington, J.A. Crystal structure of the prothrombinase complex from the venom of Pseudonaja textilis. Blood 122, 2777–2783 (2013)
Li, W. and Huntington, J.A. Crystal structures of protease nexin-1 in complex with heparin and thrombin suggest a 2-step recognition mechanism. Blood 120, 459–467 (2012).
Yamasaki, M., Sendall, T.J., Pearce, M.C., Whisstock, J.C. and Huntington, J.A. Molecular basis of α1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer. EMBO Rep. 12, 1011–1017 (2011).