The $2 million NIH MIRA grant will support Trailb


Image: This image shows the dynamic interactions of the cancer drug EGCG with the transactivation domain (TAD) of the tumor suppressor protein p53.
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Credit: UMass Amherst/Chen Lab

Jianhan Chen, professor of chemistry, biochemistry, and molecular biology at the University of Massachusetts Amherst, has received a five-year, $2 million grant from the National Institutes of Health (NIH) to support research in his Computational Biophysics Laboratory with the aim of better understanding the role of intrinsically disordered proteins (IDPs) in biology and human diseases.

The scholarship falls under the National Institute of General Medical Sciences MIRA Program that stands for Maximizing Investigators’ Research Award. It was designed to give highly talented researchers more flexibility and stability to make important scientific advances in their laboratories.

“The MIRA Prize allows us to continue working on several key issues related to the study of disordered proteins and dynamic interactions. The flexibility of this funding mechanism also allows us to pursue new research directions as they emerge,” says Chen.

Until recently, it was assumed that proteins must adopt a well-defined structure in order to fulfill their biological function. But about two decades ago, Chen explains, IDPs were recognized as a new class of proteins that rely on a lack of stable structures to function. They make up about a third of the proteins the human body makes, Chen explains, and two-thirds of cancer-associated proteins contain large, disordered segments, or domains.

“This perturbation seems to offer a unique functional advantage, and that’s why we have so many perturbations in certain types of proteins,” says Chen. “These IDPs play a really important role in biology, and when something breaks, they lead to very serious diseases like cancer and neurodegenerative diseases.”

In his lab, Chen and colleagues focus on using computer simulations to model the molecular structure and dynamics of proteins. “Displaced people are a mess; It is difficult to determine the details of their properties because they are inaccessible to traditional techniques designed to resolve stable protein structures,” he says.

Because of their chaotic state, IDPs must be described in terms of ensembles of structures, and computer simulations play a crucial role in quantitatively describing these disordered ensembles. “Our goal is really to combine simulation and experiments in collaboration with other labs to find out what are the hidden features of these disordered proteins that are crucial for their function,” says Chen. “Then we can study how these specific traits might be disrupted by disease-related mutations or conditions.”

The next step would be to develop effective strategies to combat disordered protein states. To that end, Chen’s lab will study the molecular basis of how the anti-cancer drug EGCG, an antioxidant found in green tea extract, and its derivatives interact with the p53 gene, a tumor suppressor and the key protein involved in cancer.

The key, he says, is knowing how to design drug molecules that bind to IDPs well enough to produce a therapeutic effect. Traditional, structure-based drug design strategies face significant challenges, says Chen, because IDPs do not contain stable, “drug-ready” pockets.

“We believe that targeting IDPs requires new strategies that examine the dynamic nature of IDP interactions,” says Chen. “If we can do that, it could really unlock a whole class of drugs that were previously thought impossible.”

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