Structural Biology

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Professor Wolfgang Peti, Ph. D.
Associate Professor of Medical Science and Chemistry, Brown University

Do our cells speak to one another? Maybe not literally. But the human body is made up of trillions of cells that perform a myriad of functions vital to our health and well-being. In order for our organs and systems to develop and function the way they are supposed to, those cells, and particularly the proteins that compose them, need to communicate. When they don’t, or when something goes wrong with the message, it results in disease.

The Peti Laboratory at Brown University, led by Professor Wolfgang Peti, is working to decipher the “language” of our cells.

Professor Wolfgang Peti works to solve the structure of human proteins. Photo by: RI STAC.

In our bodies, a multitude of highly specific proteins direct information transmission both between and within cells. This lays the foundation for many basic functions, from memory formation to muscle movement to organ function. Proteins direct information by adopting specific structures or shapes that allow them to interact with other proteins, DNA/RNA or small molecules-fitting together like pieces of a puzzle.

Structural biology, or the study of the 3-dimensional form of these proteins, aims to treat or cure disease by solving a protein’s structure. “By looking at the structure, we’re trying to get a fundamental understanding of the function of a protein,” explains Professor Peti. “It’s so basic-but it opens the door to so much. When you solve the structure of a protein, then you can understand how it can interact with other proteins, how the protein performs its function-or what can go wrong and, possibly, how to fix it.”

At less than a nanometer (one billionth of a meter) in size, these proteins are too small to actually see, even with the most powerful microscope. So several methods are combined to provide an accurate determination of their structure at an atomic resolution, including NMR (nuclear magnetic resonance) spectroscopy, the high-tech, high-resolution cousin of MRI used in hospitals, and X-ray crystallography.

Graduate students in the Peti Structural Biology lab. Photo by: RI STAC.

The Peti Lab’s research focuses on 3 families of proteins: serine/threonine & tyrosine phosphatases, serine/threonine kinases and innate immunity receptors. They have made significant discoveries regarding the structure and interaction of Protein Phosphatase 1, or PP1, a poorly understood but extremely important “master regulator” enzyme. PP1 interacts with many other proteins and is key to a wide range of biological functions-but is also critical in a number of diseases including cancer, diabetes, and Parkinson’s disease.

New research, in an exciting collaboration with the Page Laboratory at Brown University, focuses on the regulation of the MAP kinase p38 and the extracellular signal-regulated kinases, or ERK, pathways. “These proteins are essential for many different processes in our body, but they’re also huge cancer targets. There are tens of thousands of scientific papers on these proteins, but we actually know very little about how they are regulated at atomic resolution. But we’re making good progress.”

Understanding the structure of proteins and how they interact with one another also makes it possible to design more targeted, efficient drugs to treat illnesses. This is called “structure-based drug design.” The Peti Lab often partners with pharmaceutical companies such as Merck in the key, early stage of drug development.

“We may understand how a drug binds with a protein and how it regulates it,” explains Dr Peti. “But only if we can get a picture at an atomic resolution can we make that interaction stronger or more specific. For example, we might be able to see that if we put an extension on a drug molecule, it should bind more strongly to the protein. Knowing the structure makes it possible to synthesize a better compound, so we can make a better, more specific drug.”

The NMR machine, the high-tech, high-resolution cousin of MRI. Photo by: RI STAC.

Together with Professor Bongsup Cho from the University of Rhode Island, Professor Peti was the recipient of a 2008 STAC Collaborative Research Award. STAC funds have been instrumental to the team in providing funds for highly specialized, sensitive, and expensive equipment necessary to perform research at this level and to obtain results that help them qualify for federal grants. “The right equipment-for example the nanoliter crystallization robot, which allows us to work with extremely small quantities of proteins-multiplies our capabilities and can increase the chances of success enormously.” They have also acquired an Isothermal Titration Calorimetry machine, which measures heat associated with biomolecular interactions. Professor Peti is pleased that STAC grants also facilitate collaboration among the state’s foremost scientists and educational institutions-another key to success.

Dr. Peti, a native of Austria, has been at Brown for six years. The Peti Lab, together with the laboratories of fellow Brown researchers Dr. Rebecca Page and Dr. Gerwald Jogl, represents Brown’s first effort to implement state-of-the-art structural biology research, and is the first of its kind in the state.