The NIH's national effort, the Protein Structure Initiative (PSI), was created to find the three-dimensional shapes of a wide-range of proteins. This structural information is critical in understanding how proteins play a role in health and disease. In addition, detailed information about protein structure and function could be beneficial in designing new medicines.
Having aided in the "grand challenge" success of sequencing the human genome, scientists at Los Alamos and elsewhere recognized the next hurdle as that of understanding how cells work, and especially, what proteins do. Most genes code for proteins, and because proteins are widely used in cells -- everything from enzymes to receptors -- understanding their structure and function is essential. PSI was established in 2000 to develop innovative approaches and tools for studying protein structure as well as creating proteins from DNA sequences. Now, the focus is to rapidly determine thousands of protein structures.
"Proteins are the molecular machines of the cell. Understanding the three-dimensional shapes of proteins is an important part of therapeutic drug design, important in understanding how cells work, understanding disease and important in biotechnology," said Tom Terwilliger, principal investigator for the new center at Los Alamos.
Not all protein structures are easy to determine, however. Because of this, six of the 10 new NIH centers nationwide will focus on the more difficult proteins and new methods for studying them. The Los Alamos ISFI is one of these specialized centers. The center will develop new technologies and methodologies to determine some of these more elusive protein structures.
These will include proteins from higher organisms (such as humans) as well as proteins that combine with other proteins to form complexes, and special proteins attached to the cells' outer envelope that work to communicate with other cells.
Researchers in Bioscience Division at Los Alamos already have a wealth of experience characterizing protein structures, in fact, as the TB Structural Genomics Consortium at Los Alamos was one of the nine centers of the first phase of NIH's Protein Structure Initiative. With this expertise, researchers hope to tackle known bottlenecks in determining certain protein structures. In a type of molecular origami, every protein is folded in a very specific way, and any deviation in the folding pattern can completely change the way the protein functions. Therefore, much of the ISFI research will focus on obtaining proteins that are correctly folded: If the laboratory-produced protein structure made is not soluble in water, or does not form a crystal when it is expected to, it is likely not the correct structure. Terwilliger explained that ISFI will work to develop "powerful methods for screening whether a molecule is properly folded and whether it will crystallize."
"The goal of the project is to determine the structure of thousands of proteins representing the range of shapes of proteins in nature," said Terwilliger. As more and more structures are generated, it is possible to extrapolate families of shapes (estimated to be nearly 20,000 families), he said. The PSI would like to produce structures that are representative of each of these families. Key researchers working at the ISFI at Los Alamos include Geoffrey Waldo, who will lead the project on making proteins soluble, and Chang Kim, who will lead the Laboratory's work on protein production.
The ISFI at Los Alamos will work in collaboration with other institutions, including the University of California, Los Angeles; University of Chicago; University of Virginia; Lawrence Berkeley National Laboratory and Lawrence Livermore National Laboratory. All 10 research centers of the PSI are funded by the National Institute of General Medical Sciences (NIGMS) at the NIH and, as in the first phase, PSI centers will submit their structures and related findings to the Protein Data Bank, a public repository of three-dimensional biological structure data (http://www.pdb.org). From this databank, researchers can access a wealth of information to help them understand the function of proteins, predict shapes of unknown proteins and compare protein structures from normal and diseased tissues.
Los Alamos National Laboratory, a multidisciplinary research institution engaged in strategic science on behalf of national security, is operated by Los Alamos National Security, LLC, a team composed of Bechtel National, the University of California, The Babcock & Wilcox Company, and the Washington Division of URS for the Department of Energy's National Nuclear Security Administration.
Los Alamos enhances national security by ensuring the safety and reliability of the U.S. nuclear stockpile, developing technologies to reduce threats from weapons of mass destruction, and solving problems related to energy, environment, infrastructure, health, and global security concerns.