by Darla Brown

When the human genome was mapped, it opened up a new world to researchers by revealing man’s genetic code. Now, scientists say, the next frontier will be to understand the structure of the proteins that are encoded by the genes.

Structural biologists study and reveal the mechanisms by which cellular components carry out their processes. By isolating individual proteins and projecting them into 3-D graphic displays, drugs can be designed to target specific cellular functions.

“Disease is simply the result of cells and molecules doing things they are not supposed to do. So if we can understand the structure of the abnormal molecules, we may be able to intervene and help,” says Rodney Kellems, Ph.D., chairman of the Department of Biochemistry and Molecular Biology.

“It’s not unlike the work of a car mechanic,” he continues. “If your car breaks down, someone is able to fix it because they know the structure of the parts and how they function– structural biologists seek to understand the structure of the body at the cellular and molecular levels. This detailed structural information brings reality to the term ‘molecular medicine’ and will ultimately provide therapeutic options for the treatment of disease.”

Structural biology is not a new focus at the Medical School. There is already a Structural Biology Research Center, which is housed in the Department of Biochemistry and Molecular Biology. There is also a Center for Membrane Biology, a part of the Department of Biochemistry and Molecular Biology, which has a strong focus on the structure of membrane proteins.

“With the spotlight on structural biology, we hope to hire a significant number of new faculty who will be members of either center,” Dr. Kellems says.

A great strength of the School’s structural biology program lies in the expertise in all three primary types of technology used by scientists to determine the structure of proteins: nuclear magnetic resonance spectroscopy (NMR), X-ray crystallography, and cryo-electron microscopy.

“All three approaches give us tremendous detail in atomic resolution, and in the context of medicine, this information can be very valuable. It can provide us important opportunities for developing structure-based drug design to combat diseases,” Dr. Kellems says.

“These methods give you different information, but they complement each other,” says John Putkey, Ph.D., professor of biochemistry and molecular biology. “We are in a unique position to capitalize on findings and collaborations due to the fact that we have expertise in all three technologies.”

With electron microscopy, scientists are able to look at large molecular complexes, such as a whole virus. In favorable cases, high resolution electron microscopy can resolve individual atoms.

Technology allows researches to discern the structure of proteins and project them into 3-D models.

“Three dimensional cryo-electron microscopy is a rapidly developing area of molecular imaging, and we have considerable research strength in this important area,” Dr. Kellems says.

X-ray diffraction allows scientists to study the structure of proteins that have been crystallized.

“Protein crystallographers benefit from access to a high-energy beam line that allows them to collect high-resolution X-ray diffraction data from their proteins. We are members of a beam line consortium at the Berkeley Synchrotron, a facility that allows our crystallographers to obtain protein structures at atomic resolution very quickly,” Dr. Kellems says. “Currently our scientists take their proteins crystals to the beam line at Berkele– in a few years we expect to be able to ship proteins to the beam and view collected data in real time over the Internet.”

With NMR spectroscopy, proteins may be studied in their native state in solution and in motion.

“Structure determines function,” says Sudha Veeraraghavan, Ph.D., assistant professor of biochemistry and molecular biology. “Determining the structural model gives us a visual insight into how we can modify the function and determine drug design. NMR and crystallography are complimentary high resolution methods that precisely describe the positions of atoms or nuclei in a molecule and help solve the puzzle of how function is determined by structure.”

“If you can’t get the protein to crystallize, you can get 3-D information from it via NMR, and modify it in solution to see how it interacts,” Dr. Putkey adds.

In recent years, there has been an increase effort at the national level in furthering this research.

“There is emphasis on membrane protein structures in the National Institutes of Health roadmap initiative because of the large numbers of biomedically important receptors, channels and pumps - nearly 30% of the human proteome consists of membrane proteins,” says John Spudich, Ph.D., director of the Center for Membrane Biology.

The Medical School plays a major role in the field not only in the Texas Medical Center but in the surrounding Houston area as a member of the Gulf Coast Consortia for Membrane Biology and for Structural Biology, which includes Rice University, The University of Texas M. D. Anderson Cancer Center, the University of Houston, The University of Texas Medical Branch, and Baylor College of Medicine.

“There are not many places that have such organized centers and strengths in membrane structural biology as we do here at the Medical School, so we are well positioned to attract the best young scientists to build on our expertise,” Dr. Spudich adds.

With expertise on hand and the promise to add more faculty and space, the Medical School is poised to become an international leader in this burgeoning field.

“There are exciting new developments in membrane protein crystallization, and we’re playing a role in developing that much needed technology. Structural biology is one of the most promising new frontiers in biomedical research,” Dr. Spudich says.