In the old days, finding a new drug was more trial and error than science. But nowadays rational drug design is quickly taking the error out of the process. Scientists can now study a cell’s protein machinery and create small molecular “tinker toys” that interact with it and modify how it functions.
In a recent study, published in the Proceedings of the National Academy of Sciences, a multidisciplinary team led by researchers at UC San Diego determined the structure of a protein (MitoNEET) that shows potential as a target for the development of new drugs to treat diabetes.
The researchers say that MitoNEET has a novel three-dimensional structure that makes it a particularly interesting candidate for the design of innovative compounds that
can bind to it.
“This is the first time that a protein like this has ever been found,” says Patricia Jennings, a professor in the department of chemistry and biochemistry who led the study along with Mark Paddock, M.S. ’84, Ph.D. ’91, a project scientist in the physics department. “It is a brand new structure, a unique beast, which makes it an exciting target for structure-based drug design.”
“Our work may provide a basis for the design of newer diabetes drugs that have potentially greater specificity and fewer side effects than existing ones,”
adds Paddock.
The highly collaborative research team, which also included researchers from UCSD’s School of Medicine, the Stanford Synchrotron Radiation Laboratory and
the Hebrew University of Jerusalem, determined that mitoNEET is an iron-sulfur protein. Iron-sulfur proteins have a variety of functions, including electron transfer, which is critical to cell metabolism and the storage and transport of iron. In its free state, iron is highly toxic to cells.
MitoNEET’s iron-sulfur cluster is loosely bound. When mitoNEET binds to the type 2 diabetes drug Actos®, the iron-sulfur cluster becomes more stable. The new findings suggest that Actos® and similar drugs may protect cells from the damaging effects of free iron by keeping the iron-sulfur cluster attached
to mitoNEET.
Given mitoNEET’s structure, location and properties, it could also play a role as a sensor
of oxidative stress in the cell. Oxidative stress—the accumulation of reactive
compounds that can damage cells —is a problem in many diseases including diabetes.
“MitoNEET may be an example of an ever-increasing group of proteins found to have more than one function,” says Paddock. “I think we are at the beginning of what is sure to be an interesting and biologically important puzzle.”
— Sherry Seethaler
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