An innovative method that allows increased success and speed of protein crystallization a crucial step in the laborious, often unsuccessful process to determine the 3-dimensional structure unique to each of the body's tens of thousands of folded proteins has been developed by researchers at the University of California, San Diego (UCSD) School of Medicine and verified in tests with the Joint Center for Structural Genomics (JCSG) at The Scripps Research Institute (TSRI) and the Genomics Institute of the Novartis Research Foundation in La Jolla, California.

Described in the Jan. 20, 2004 issue of the journal Proceedings of the National Academy of Sciences (PNAS)*, the method, which employs a UCSD invention called enhanced amide hydrogen/deuterium-exchange mass spectrometry, or DXMS, rapidly identifies small regions within proteins that interfere with their ability to crystallize, or form a compact, folded state. The investigators demonstrate that once these regions are removed by what amounts to "molecular surgery", the proteins then crystallize very well.

"Although the sequencing of the human genome gave us the code for genes that are the recipes for proteins, we need to see and understand the folded shape taken by proteins to determine how they work as the fundamental components of all living cells," said UCSD's Virgil Woods, Jr., M.D., the inventor of DXMS, senior author of the PNAS article and an associate professor of medicine. "Definition of a protein folded structure is of great use in the discovery of disease-targeting drugs. Furthermore, when we're able to identify incorrectly folded proteins in disease states, such as Alzheimer's, cystic fibrosis and many cancers, we may then be able to design drugs that encourage proper folding or block the misshapen protein."

Unfortunately, many proteins do not naturally form a single, compact state in solution and hence, they are often highly resistant to crystallization, which is required f
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Contact: Sue Pondrom
spondrom@ucsd.edu
619-543-6163
University of California - San Diego
15-Jan-2004

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