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Designer Molecules: Largest Protein Ever Created From Scratch Has Implications For Novel Drug Delivery And Diagnostics

For the last decade, scientists have been trying to accurately synthesize substances with shapes that mimic biological molecules, specifically proteins that drive important biochemical pathways in humans. So far, these attempts have made moderate strides, both in terms of size of the designed protein and the precision with which it folds from a string of amino acids to its final three-dimensional structure. Now, researchers at the University of Pennsylvania Medical Center have created the largest protein from scratch, with both a stable and predictable shape.

"The ability to do this really takes us out of the realm of tinkering with existing proteins to engineering entirely new proteins and polymers," says senior author William F. DeGrado, Ph.D., professor of biochemistry and biophysics. "We have shown that it is now possible to design a protein with a well-defined three-dimensional structure." The Penn group's findings appear in the May 11 issue of the Proceedings of the National Academy of Sciences.

DeGrado notes that implications of this advance in protein design could be as broad as those for natural proteins -- from manufacturing entirely new polymers for industrial catalysts to creating new pharmaceuticals.

To design a protein, scientists generally work backwards from nature in a two-step process. They first choose an existing three-dimensional protein structure and then, using complex computer programs, find a new sequence of amino acids that folds into the same shape as the natural protein. The Penn team's approach is one step removed from that. "We asked: Can we generate proteins that are inspired by nature but have no direct natural equivalent?," explains DeGrado.

The protein -- called alpha-3D -- was designed, produced, and characterized by Scott Walsh, a doctoral student in DeGrado's lab. Alpha-3D is a bundle of three counterclockwise-coiling helices whose general shape was inspired by a protein found in the common h
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Contact: Karen Young Kreeger
kreeger@mail.med.upenn.edu
215-614-0290
University of Pennsylvania School of Medicine
11-May-1999


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