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Blood clot buster in atomic detail

MONASH (AUS) — Researchers have discovered how an enzyme that destroys blood clots is switched on, unlocking a century-old atomic riddle.

The findings could lead to new treatments for clotting and bleeding disorders, and some cancers.

In a study published in Cell Reports, researchers at Monash University along with colleagues at the Australian Synchrotron show how the protein plasminogen is converted into plasmin, an enzyme that removes disease-causing clots and clears up damaged tissue.

Clinicians currently use drugs called plasminogen activators to generate plasmin in treating heart attack and stroke patients.

Further, as plasmin is responsible for breaking down tissue barriers in cancer, a large number of researchers worldwide are developing plasmin inhibitors as anti-cancer therapeutics.

James Whisstock, a professor at Monash, says scientists had been trying for nearly a century to understand how plasminogen is activated to plasmin.

“Now we can see the atomic details of the plasminogen we can finally get a detailed picture of how the whole system works and how plasmin is produced,” Whisstock says.

Co-lead author Ruby Law of Monash says plasminogen displayed unexpected behavior.

“A casual look at the structure would suggest that plasminogen seems to completely guard its activation site. However, we found that one part of plasminogen seems to be very unstable and can transiently pop open a fraction—a little like a child playing a game of ‘peek-a-boo’,” Law says.

“Proteins in the blood clot bind to this part of the molecule when it is exposed, with the result that plasminogen is trapped in a form that can be converted to plasmin.”

Tom Caradoc-Davies from the Australian Synchrotron says the extremely intense X-ray crystallography beamline at the Synchrotron made it possible to determine the atomic structure of plasminogen.

“Plasminogen only yielded its secrets when exposed to the most focused and powerful X-rays the synchrotron can currently produce—technology which has only become available in the past few years,” says Caradoc-Davies.

Study co-leader Paul Coughlin of the Australian Centre for Blood Diseases at Monash says that until now, the molecular details of current plasminogen-activating drugs to treat stroke had not been understood.

“There are a large number of drugs in current clinical use, or in late stages of development, that function to convert plasminogen to plasmin. Now, we can use our current discoveries to improve the efficacy of these therapeutics,” says Coughlin.

Stroke is the third leading cause of death in the United States, according to government statistics, claiming more than 140,000 lives each year. It is the leading cause of long-term, serious disability.

More news from Monash University: www.monash.edu.au/news/latest

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