May 14, 2004
LSI builds structural biology dream team
ANN ARBOR, Mich.—Form is said to follow function in architectural design, but in nature, the form and the function are often the same thing. Individual molecules in the tiny, complex world of the living cell interact and fit together very specifically, based on their three-dimensional shapes.
The science of figuring out what those shapes are and how they fit together is known as structural biology, and it holds great promise for unraveling a host of human diseases. Misshapen proteins are known to be a factor in Alzheimer’s and Parkinson’s, diabetes, high cholesterol, mad cow disease, bacterial infections and are probably involved in countless other conditions as well.
The Life Sciences Institute at the University of Michigan is building one of the nation’s foremost teams of structural biology researchers and starting a Center for Structural Biology.
With the hiring of Janet L. Smith from Purdue University and Gabrielle Rudenko from the University of Texas Southwest Medical Center, the LSI now has a core of five leading structural biologists clustered around state-of-the-art facilities on the third and fourth floors of the new LSI building.
“I love to think about biology in terms of structure,” said Smith, who recently participated in a team effort to figure out how bacteria convert sunlight into energy. Her current structural work focuses on an enzyme that catalyzes chemical reactions, and on the structures used by RNA-based viruses including West Nile, yellow fever and dengue.
The mainstay technology used by Smith and other structural biologists is x-ray crystallography. Though today’s equipment is much better, this is essentially the same method used by Rosalind Franklin to take the fuzzy pictures of DNA from which James Watson and Francis Crick deduced the molecule’s elegant double-helix shape more than 50 years ago.
A focused beam of x-ray light is shot at a crystal of pure protein. Sensitive detectors then capture the scatter pattern that reflects off the individual atoms in that crystal. LSI structural biologist Jeanne Stuckey likens it to shining a light on a disco ball. With some complex math called “fast Fourier transforms,” crystallographers are able to infer the relationships between atoms in the crystal by the way the scattered light came off it, and then go on to infer from that the shape of the protein.
Stuckey’s lab on the third floor of LSI has an x-ray crystallography beam that is about 10 feet long. But at the Argonne National Laboratory’s particle accelerator southwest of Chicago, Michigan researchers are about to begin making images with a new x-ray beam line that will be a billion times brighter than the tabletop version at the LSI. This will allow them to capture finer resolution of images, and robotic sample handing machines will enable much higher throughput of crystals.
The heavy math is only half the battle. Before they can take the picture, researchers need to grow a nice crystal of 100 million proteins “aligned in a beautiful, symmetrical form,” Stuckey said. In theory, at least, any protein can be crystallized, but purifying the protein and then finding the right conditions to grow a high quality crystal can be arduous. “It takes a lot of patience,” Stuckey said.
Janet Smith will lead a new Protein Production Facility on LSI’s third floor that should streamline and speed up the process by using a lot of automation. The protein production facility will serve both the Center for Structural Biology and researchers in the newly established Center for Chemical Genomics.
“We use automation to try many things at once for finding ideal crystal-growing conditions,” Smith said. “That way, we don’t burn up all our student and post-doc time just growing crystals.”
The Life Sciences Institute’s structural biologists are:
Rowena Matthews -- In work ranging from organic chemistry to genetics, Matthews investigates the role vitamins play in the chemical reactions in the body. Her understanding of folic acid’s biochemical role in heart disease led to a federal policy requiring U.S. grain products to include folic acid supplements. Since the adoption of the policy, the Centers for Disease Control estimates the folic acid supplements are preventing nearly 50,000 deaths annually from stroke and heart attack. She is a research professor in LSI and biophysics and a Distinguished University Professor in Biological Chemistry.
Gabrielle Rudenko – A structural examination of protein molecules is helping Rudenko to understand the brain. Her latest work is focused on a class of proteins that help the brain recover from physical and chemical insults. Rudenko, who moved into her LSI lab in April, d also has plans to study macromolecules that are crucial to the brain, and influence how we function and feel. She is an assistant research scientist in LSI and an assistant professor in pharmacology.
Janet Smith – Smith has worked on difficult puzzles of the three-dimensional shapes of biomolecules across a wide range of biology. Her current work focuses on some very dynamic enzyme systems where a single molecule may be involved in several different chemical reactions. She is also working on the structures within RNA viruses that enable them to evade immune systems and steal resources from healthy cells. She is a research professor and leader of the protein production facility in the LSI, professor in the Department of Biological Chemistry.
Jeanne Stuckey – In addition to supervising the x-ray crystallography lab that assists researchers all over the U-M campus with their structural biology questions, Stuckey is working on the structure of proteins involved with programmed cell death. She has contributed ?structures to our understanding of arthritis and diabetes, and the molecular tool kit of Yersina pestis, the virulent bacterium that caused the Black Plague. Stuckey is an assistant research scientist in LSI, biophysics, and biological chemistry.
Zhaohui Xu – Calling on tools from biology, chemistry and physics, Xu works to understand how proteins become folded into their proper shapes and are delivered to the right place in the cell. His lab has found that molecular “chaperones” assist folding and transportation at almost every step. Xu is also turning his attention to naturally occurring enzymes and the possibility of slightly changing their folding to alter their properties. Xu is an assistant research scientist in LSI and an assistant professor inbiological chemistry.
Contact: Karl Leif Bates