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NIH funds powerful magnet for protein studies

– The National Institutes of Health awarded the University of California, Berkeley, nearly $6 million this week to purchase the most powerful magnet available today for studying protein structure and to push its limits in discovering the structure and dynamics of biomolecules.

The nuclear magnetic resonance (NMR) machine, with wire coils cooled by liquid helium to a few degrees above absolute zero, will put UC Berkeley researchers and other local scientists at the forefront of efforts to understand how proteins are put together and how they change shape as they do their job. Such understanding is essential if researchers are to tackle diseases and develop drugs to treat them.

The five-year, $5.9 million grant - one of two grants for state-of-the-art NMRs announced by the National Institute of General Medical Sciences this week and one of six funded by the institute in the last year - will be run by UC Berkeley researchers who are part of the California Institute for Quantitative Biomedical Research (QB3). QB3, a collaboration between UC Berkeley, UC San Francisco and UC Santa Cruz, is one of four California Institutes for Science and Innovation (Cal-ISI) created in 2000 at the University of California through a partnership of state and industry support.

"One of the central themes in QB3 is using structural biology to understand how biological molecules - proteins, nucleic acids and carbohydrates - carry out their function," said project leader David Wemmer, UC Berkeley professor of chemistry and a faculty scientist at the Lawrence Berkeley National Laboratory. "This NMR system will allow us to push the envelope to see what we can learn about protein structures and the dynamics of structures and how they interact with other things."

The several-ton instrument, a 900 Megahertz (MHz) NMR which uses a powerful 21 Tesla magnetic field, will be housed in the basement of UC Berkeley's major new research building, the Stanley Biosciences and Bioengineering Facility, begun this spring and scheduled for completion in 2006.

"Researchers at the Institute for Quantitative Biomedical Research are studying some of the molecules that biomedical researchers find most tantalizing - very large complexes of proteins, and of proteins with nucleic acids, that control normal cell behavior and influence diseases such as cancer and AIDS," said Janna Wehrle, PhD, program director at the National Institute of General Medical Sciences, which supports basic biomedical research that lays the foundation for advances in disease diagnosis, treatment and prevention.

"To study these challenging complexes requires the world's most advanced NMR instrumentation. We are awarding this grant for the 900 MHz instrument to boost their ability to meet this challenge."

The users, including scientists from Stanford University, UC San Francisco, UC Davis, Lawrence Livermore National Laboratory and Genentech, Inc., plan to investigate many large molecules of importance in disease as well as the normal functioning of cells. For example, Wemmer and UC Berkeley colleague John Kuriyan, professor of chemistry, plan to look at large proteins called kinases that regulate many processes in the cell and play a big role in cancer. Kuriyan has long studied kinase structures by coaxing the protein into forming a crystal and then X-raying the crystal to determine the protein's turns and folds.

"Using NMR to probe dynamics will complement the structural information Kuriyan has been getting already by X-ray crystallography," Wemmer said. "The challenge is that the kinases are large and quite complicated, and hard to get in high concentration, all of which challenge the ability of NMR. A high-field system like this will allow us to push the envelope out to include molecules like this we can't do with current technology."

Other researchers plan to look at the 3-D structure of large molecular complexes of RNA, such as pieces of ribosomes that translate the genetic code into protein, or signaling proteins called cytokines.

The 900 MHz instrument, producing a magnetic field 400,000 times that of the Earth, is a big advance over the previous generation of 800 MHz instruments, Wemmer said.

"As the magnetic field has gone up, there is no question that doors have opened to new research," he said. "But there is always the issue of cost benefit. NIH is funding these to find out how far you can push the limits."

NMR allows study of molecules in solution and thus closer to their environment in the cell. In addition, NMR can follow the structural changes in a molecule, from tiny shifts in an atom to major unfolding and refolding.

"In terms of characterizing the extent of motion - how much a molecule moves and what the time scale is - NMR is unsurpassed," Wemmer said.

Samples of protein, carbohydrate or RNA in solution are placed in the 2-inch bore of the magnet and sometimes left for two weeks as the machine measures the environment of each hydrogen atom in the sample. Intensive computer manipulation is needed to extract a complete picture.

The machine itself will cost about $5 million, Wemmer said, with the remainder of the NIH funds supporting operations. All users will be required to deposit their data in the Protein Data Bank so all data collected will be public.