Molecular discovery loosens the grip of thrombosis

4 September 2009

Researchers part-funded by the Wellcome Trust have deduced that a powerful inhibitor molecule blocks a key receptor involved in blood clotting by loosening its grip.

The insight could pave the way for new treatments, free of side-effects, to prevent thrombosis, according to the researchers from the University of Nottingham and Monash University in Australia. Thrombosis is caused by harmful clots in the blood that obstruct the flow of blood, which can lead to heart disease and stroke,

Blood clots form when platelets - small, cellular blood fragments - clump together. A key part of this is the interaction of a platelet receptor, glycoprotein Ib, and a blood plasma protein called von Willebrand factor.

The receptor forms a 'hand', with the 'fingers' and 'thumb' firmly clasping von Willebrand factor, enabling platelets to stick together. However, research has shown that this grip can be disrupted by an inhibitor molecule, known as OS1.

The new study reveals that the OS1 actually changes the shape of the receptor by binding to a separate site on the palm of the receptor 'hand'. This bends the 'thumb' region back so it cannot bind to von Willebrand factor, thus preventing platelet aggregation.

Knowing how this interaction works will help researchers find new, improved ways to treat thrombosis, says Dr Jonas Emsley from the University of Nottingham, who led the study.

"Current anti-coagulants for treating thrombosis in heart attacks and strokes, such as heparin, target multiple proteins. These often also play a central role in healthy blood clotting and hence are more prone to cause side effects such as bleeding," said Dr Emsley.

"Studies suggest that targeting glycoprotein Ib with anti-platelet agents could avoid these side effects, so this will be of great interest in the drive to discover novel anticoagulant therapies."

The discovery could also help treat other diseases. Glycoprotein Ib is part of an extended family of proteins mediating protein-protein interactions in a variety of diseases such as asthma, atherosclerosis, Alzheimer's disease and leukaemia.

Image: Colour-enhanced scanning electron microscope image of a blood clot at high power, showing a prominent white blood cell in the centre. Credit: David Gregory and Debbie Marshall, Wellcome Images

Reference

McEwan PA et al. Glycoprotein Iba inhibitor complex structure reveals a combined steric and allosteric mechanism of von Willebrand factor antagonism. Blood 2009.