image: Doug Rees will head the new Center for the X-ray Structure Determination of Human Transporters. view more
Credit: Caltech/Bob Paz
PASADENA, Calif.—The National Institutes of Health (NIH) has awarded $11.5 million to a consortium of research institutions led by the California Institute of Technology (Caltech) for the creation of a center for the study of membrane-protein structures.
The center—called the Center for the X-ray Structure Determination of Human Transporters—is one of nine new membrane-protein centers established by the NIH to "solve the structures of these elusive yet very medically relevant proteins," says Ward Smith, director of the NIH's Protein Structure Initiative (PSI), which is supporting the Caltech-led center. "This center brings together a powerhouse of investigators who, working in collaboration, will shed new light on the basic biology of these important membrane proteins and their potential role in treating disease."
"All cells are surrounded by membranes," says Doug Rees, the Roscoe Gilkey Dickinson Professor of Chemistry at Caltech and a Howard Hughes Medical Institute investigator, who has been named principal investigator for the new center. "The cell membrane serves as a permeability barrier that regulates the flow of matter, information, and energy between the inside of the cell and the external environment. Transporters are specialized membrane proteins that mediate the passage of virtually every molecule in and out of cells."
These membrane proteins are "really important, biologically," he adds. "Twenty-five percent of all proteins encoded in the human genome are membrane proteins, and over half of all drugs work on membrane proteins. Transporters are vital to the biology of all cells, and a variety of diseases occur when these processes are disrupted, as in several genetic disorders or the up-regulation of multidrug resistance transporters by tumor cells."
Specifically, Rees and his new center will be focusing on membrane transporter proteins; scientists have identified 521 of these specialty proteins in humans. The team's goal, he says, is to "try to determine the structures of as many as we can to help understand how transporters function as molecular pumps moving molecules across membranes."
Putting together a detailed structural picture of a protein is no easy task; Rees says that finding the structure of a single such protein normally takes the same amount of time—five years—as the period over which the center is being funded.
But by working to "come up with an efficient pipeline for streamlining the protein- structure determination process," Rees says, their hope is that they will be able to increase the rate of discovery by at least an order of magnitude. "It's an entirely different approach," he adds. "In the end, we're hoping to find 10 or 15 structures."
The point of all this effort, Rees says, is to "connect a protein's structure with how it functions in a biological system." This structure-based approach to biological function was pioneered at Caltech by Linus Pauling starting in the 1940s, Rees adds, and has guided most subsequent advances in understanding the molecular mechanisms of biological systems.
In other words, to really understand how a protein works, you have to know what it looks like. "And that information," Rees says, "is really important in designing therapeutics that target the protein."
In creating and running the center, Rees will be collaborating with William Clemons Jr., assistant professor of biochemistry at Caltech, as well as with two former Caltech researchers: Geoffrey Chang of the Scripps Research Institute, who was a postdoc in Rees's laboratory, and Michael Stowell of the University of Colorado, who received his PhD in chemistry at Caltech. Researchers from the Sanford-Burnham Medical Research Institute, UC San Diego, Stanford University, and Texas Tech will add their expertise.
The PSI started in 2000 with the main goal of developing highly efficient, or high-throughput, methods for revealing the structures of many different proteins. The Center for the X-ray Structure Determination of Human Transporters is part of the PSI's third phase, PSI:Biology. For the complete list of awards, see the PSI:Biology Network page at http://www.nigms.nih.gov/Initiatives/PSI/psi_biology/.