Australian Synchrotron discovers how plasminogen is activated in the body

Researchers at Monash University have used X-ray beams created by the Australian Synchrotron (AS) to discover how enzymes work to dissolve blood clots and clean up damaged tissue in the body - a finding that could ultimately lead to a reduction in the number of heart disease-related deaths occurring each year as a result of blood clots.

Dr Tom Caradoc-Davies, Principal Scientist on the Macromolecular Crystallography beamline, said the results came after months of collaboration between Monash University researchers and the AS science group.

“We strongly believe these findings will lead to the design of better antiblood-clotting drugs and drugs to actively treat bleeding disorders and certain cancers,” said Dr Caradoc-Davies.

The Australian Synchrotron provides highly specialised research capabilities, unique within the Southern Hemisphere. Using the facility’s Micro Crystallography and Small and Wide X-ray Scattering research stations, scientists were able to identify the structure of a blood protein called plasminogen, a precursor of the enzyme plasmin, which assists in dissolving blood clots and is also implicated in some cancers.

The findings were published in the science journal Cell Reports, in a paper titled ‘The X-ray crystal structure of full length Human Plasminogen’ - the first of its kind in the world.

“We knew that other research groups, some representing major pharmaceutical interests, were working on the same problem and our competitive advantage lay in being able to use the Australian Synchrotron to ‘identify’ the crystal structure of plasminogen,” said Dr Caradoc-Davies.

“Because we could look at the atomic nature of plasminogen using the synchrotron, we were able to answer an almost century-old scientific question - how is plasminogen really activated in the body.”

Professor James Whisstock, who led the researchers from Monash University, said the findings illustrated just how important the Australian Synchrotron was to modern science and Australia’s ability to compete at an international level.

“In the past, the molecular details of plasminogen-activating drugs used to treat strokes were not entirely understood. This latest discovery by Monash and the AS science team means drug companies will now be able to finetune their development of next-generation anti-clotting/‘clot busting’ drugs and cancer treatments,” said Professor Whisstock.

Historically, clinicians had used drugs to convert plasminogen into plasmin to treat patents in the hours immediately after heart attack or stroke. Plasmin inhibitors had also been used as anticancer therapeutics. The true nature of how these drugs affected plasminogen, however, was not known until the results of this study were finalised.