A UCSF research team led by Department of Bioengineering and Therapeutic Sciences Chair and Professor James Fraser, PhD, and Department of Pharmaceutical Chemistry Professor William DeGrado, PhD, has pioneered a breakthrough approach to designing proteins with targeted functions, which could lead to simpler ways to improve enzymes and medications, among other uses, according to a new study published in Nature Chemistry.

Using bright X-rays from the Department of Energy’s SLAC National Accelerator Laboratory and Lawrence Berkeley National Laboratory (Berkeley Lab), researchers for the first time combined X-ray studies of how small molecule fragments bind to designed proteins, known as “crystallographic fragment screening,” with a method used to design proteins called “directed evolution.”  

Their method generated new insights that allowed the team to turn a single designed protein into two new proteins with completely different functions, one of which is the most active designed enzyme to date.

The researchers matched fragment screening with X-ray crystallography at the national laboratories’ light sources. Used extensively in drug discovery, the technique reveals which small molecular fragments bind to a target protein and where they bind. Although long used for natural proteins, crystallographic fragment screening had not been used for designed proteins, until now.

“Our novel protein design strategy simultaneously explores the landscapes of chemical space and sequence space, which helps design functional proteins rapidly,” said Sagar Bhattacharya, PhD, postdoctoral researcher at UCSF and an author on the paper.

Read the full article about how our researchers are collaborating across disciplines and institutions to potentially simplify the making of improved drugs and catalysts.