For the first time, scientists have created, entirely from scratch, a protein capable of binding to a small target molecule. Researchers from the University of Washington School of Medicine report the advance in the Sept. 12 issue of the journal Nature.
Previously, such small-molecule binding proteins have been made by altering proteins already existing in nature. That approach significantly limited the possibilities. The ability to make such proteins from scratch, or “de novo,” opens the way for scientists to create proteins unlike any found in nature. These proteins can be custom-designed with high precision and affinity.to bind to and act on specific small molecule targets.
The lead authors of the paper are Jiayi Dou and Anastassia A. Vorobieva, both senior fellows in the lab of senior author David Baker, professor of biochemistryat the UW School of Medicine and director of the Institute for Protein Design at UW Medicine. Baker is also an investigator at the Howard Hughes Medical Institute.
The technique should have wide application in research, medicine and industry, Baker said.
“The successful de novo design of custom-built proteins with small-molecule binding activity sets the stage for the creation of increasingly sophisticated binding proteins that will not have the limitations seen with proteins that have been designed by altering existing protein structures,” he explained.
To make the protein, the researchers had to achieve another first: Creating from scratch a cylinder-shaped protein called a beta-barrel. The beta-barrel structure was ideal because one end of the cylinder could be designed to stabilize the protein, while the other end could be used to create a cavity that can serve as the binding site for the target molecule.
