BERKELEY, CA — The National Institute of General Medical Sciences (NIGMS) has launched the "Protein Structure Initiative" with the intent to determine the form and function of thousands of proteins over the next decade. The initial phase of this initiative has started with the awarding of seven new grants, each totaling around $4 million for the first year, including one to Sung-Hou Kim, a chemist who heads the Structural Biology Department of the Physical Biosciences Division at the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab).

PROTEIN SHAPES REVEAL RECURRING STRUCTURAL MOTIFS CALLED "FOLDS" THAT HELP DEFINE PHYSICAL AND CHEMICAL PROPERTIES. COMMONLY SEEN FOLDS INCLUDE BETA-SHEETS OR RIBBONS (TOP TWO IMAGES), ALPHA-HELICES (THIRD FROM TOP), AND COMPLEX GLOBULAR CONFORMATIONS (BOTTOM).

"This project can be viewed as an inventory of all the protein structure families that exist in nature," said Dr. Marvin Cassman, NIGMS Director, in announcing the grants. "We expect that this effort will yield major biological findings that will improve our understanding of health and disease."

Cassman said his agency, which is one of the components of the National Institutes of Health, expects to spend approximately $150 million on these inaugural seven grants over the next five years. This would make NIGMS the single largest funding agency of structural genomics, the emerging scientific field in which the identification of gene-coding DNA sequences are combined with 3-D structural images to determine protein functions.

Said John Norvell, director of the NIGMS Protein Structure Initiative, "These research centers are true pilots. Each will include every experimental and computational task of structural genomics and will develop strategies for use in the subsequent large-scale research networks. By the fifth year of the award, we expect each pilot center to reach a production level of 100 to 200 protein structures annually, which is significantly greater than the current rate of protein structure determination."

Sung-Hou Kim, who in addition to his Berkeley Lab appointment is also a professor with the College of Chemistry at the University of California's Berkeley campus, is a world authority on protein crystallography. He has been a pioneer in structural genomics and one of the leading advocates for grouping proteins into families on the basis of recurring structural patterns known as "folds," and using these fold families to help predict protein functions.

Other leaders working with Kim on this project include Paul Adams, Steve Brenner, Thomas Earnest, Rosalind Kim, and David Wemmer, of Berkeley Lab, plus Clyde Hutchison of the University of North Carolina, and David McKay of Stanford.

With the completion of a "working draft" of the human genome, scientists are now busy identifying the genes within the sequences of those three billion DNA bases. The next step is to determine the purpose of those genes, which means determining the molecular and cellular functions of the proteins they code for. Proteins are the building blocks of living cells and control much of the biochemical processes that are vital to all life.

The prevailing method for predicting a protein's function is to compare the sequence pattern of its DNA to the DNA sequence patterns of genes whose functions have already been identified. A major problem to relying exclusively on this approach is that while proteins in different organisms may have similar form and function (the two go hand-in-hand for proteins), the DNA sequencing patterns of their genes may be dramatically different.

As an alternative or supplemental approach, Kim and other crystallography leaders have proposed that the molecular functions of a protein can also be predicted from the folds that underlie all protein architecture. While the number of different proteins may number in the hundreds of thousands, most biologists agree there are probably less than ten thousand distinctly different types of folds and that a majority if not all proteins will belong to one of these fold families.

Under the protein structure initiative being launched by NIGMS, the seven grant recipients will each work with representative protein populations obtained from organisms whose entire genomes have been sequenced. The idea being that through the eons, families of proteins have selectively evolved into the structural shapes best suited to do their specific jobs. Kim and his group will work with two closely related bacteria, Mycoplasma genitalium and Mycoplasma pneumoniae. The former contains the smallest known genome of any free-living organism and infects the human genital and respiratory tracts. The latter causes a form of pneumonia.

To identify the structures of the full complement of proteins that make up these two "minimal organisms," Kim and his colleagues will primarily use x-ray crystallography, backed by nuclear magnetic resonance and computation. In x-ray crystallography, a beam of x-rays is sent through a protein's crystal. The crystal's atoms cause the incoming photons to be scattered, creating a diffraction pattern that computers can translate into a 3-D image of the protein's structure. Kim and his colleagues will have access to the Berkeley Center for Structural Biology which features one of the world's premier x-ray beamlines for protein crystallography at Berkeley Lab's Advanced Light Source (ALS).

The ALS is an electron synchrotron that produces beams of x-rays and ultraviolet light for scientific research, which are a hundred million times brighter than those from the best x-ray tubes. This high brightness reduces the time required to collect a complete set of data for a single protein from what had once been months or even years using an x-ray tube, to a matter of weeks, days, or even hours.

"The use of a synchrotron radiation source such as the ALS can dramatically decrease the time required to solve novel protein structures," Kim has said. "It makes a clear and compelling case that protein crystallography can provide a foundation for structural genomics."

As a major part of their effort, Kim and his collaborators will look to reduce the time required to produce and set protein crystals up in the beamline, illuminate them with x-rays, and collect the data. Automation of the entire process, including the use of a unique crystal-growing robotic system designed and built by a team of engineers and technicians led by Joe Jaklevic with Berkeley Lab's Engineering Division, will be a key.

The project will also benefit from automation tools being developed and built to increase the throughput and efficiency of the structural determination process, including robotic crystal mounting and alignment and expert computation systems.

Data collected by Kim and his collaborators, along with that collected by the other NIGMS grant recipients is to form the foundation of a public resource linking sequence, structural, and functional information. NIGMS will make this information be available on the Internet to all scientists.

Berkeley Lab is a U.S. Department of Energy national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California.

Additional information:

• The quest ahead: resolving the structure of the machinery of life
• The National Institute of General Medical Sciences (NIGMS) announcement