Fraser named Searle Scholar, will shine new light on protein shapeshifting

Biophysicist James Fraser, PhD, has been named a 2014 Searle Scholar. His laboratory will be awarded $300,000 in funding over the next three years to support his research into more accurately and precisely describing the ways that protein molecules change shape to carry out the functions of life in our bodies.

The prestigious awards are given annually to 15 young scientists nationally “who are bringing new technologies and new perspectives to address some of the biggest questions in biomedical sciences,” said the program’s scientific director, Douglas Fambrough, PhD.

Fraser is a faculty member in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.

To make new drugs to treat diseases, scientists create small molecules that bind to protein molecules to alter their activities—inhibiting or activating them. But such structure-based drug design is challenging because proteins are flexible molecules and, beyond their basic chemical configurations, routinely take on different shapes—called conformations—in order to carry out their functions.

Over the past half-century, scientists have determined the 3-D chemical structures of proteins and some of their conformations by coaxing them to form crystals, shining ever-brighter x-rays through them, and then analyzing how they alter (diffract) the beams.

But the accuracy of this method—x-ray crystallography—can be limited by the need to avoid damage from the x-rays. Consequently, scientists often freeze protein crystals, which can alter their shapes and prevent them from displaying some of the relevant conformations they might take on in our bodies.

Fraser has developed methods to perform x-ray crystallography at room temperature as well as new ways to computationally analyze the resulting conformations. Both approaches seek to better capture the variety of shapes that proteins adopt to perform their functions and how they shift between them. This will help scientists understand how protein conformations are disturbed by disease and how to design more effective drugs that better account for conformational change in their protein targets.

In his Searle-funded research, Fraser will apply a revolutionary new light source to his study of protein shapeshifting. The Linac Coherent Light Source is an x-ray laser that is a billion times brighter than the most powerful previous sources, according to Stanford University’s National Accelerator Laboratory where it is based. And that light is generated in ultrafast pulses, akin to camera flashes, that can capture crystallographic measures of molecular activity in less than a tenth of a trillionth of a second. The speed of those pulses means that images of proteins, including their different conformations, can be captured before x-ray damage takes place.

“The special properties of this light source will enable us to move from taking blurred individual snapshots of proteins to making molecular movies that enable us to watch proteins as they work,” says Fraser.