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ShareDec. 24, 1999 — WALTHAM, Mass. -- Atom by atom, a Brandeis University researcher and her colleagues have unmasked the structure of ephemeral protein "switches" that play a critical role in transforming mild-mannered bacteria into lethal parasites. The finding, reported in the Dec. 23 issue of the journal Nature, raises the prospect of a novel kind of antibiotic to fill the void left by growing resistance among many bacteria to traditional drugs.
The research, led by Brandeis biochemist Dorothee Kern, also involved scientists from the University of Wisconsin, Lawrence Berkeley National Laboratory, and the University of California at Berkeley.
Current-generation antibiotics, which kill off normal strains of bacteria while leaving resistant ones unaffected, essentially select for the survival of resistant strains, sometimes inducing resistance in as little as six months. The protein family Kern describes in the Nature paper represents a potential target for a whole new class of antibiotics to specifically prevent pathogenic bacteria from becoming virulent and attacking the body's cells.
"Most conventional antibiotics work by inhibiting processes essential to cell viability, such as DNA translation or the assembly of cell membranes," says Kern, an assistant professor of biochemistry at Brandeis. "Few attempts have been made to target the mechanisms by which pathogenic bacteria become virulent and infect host cells."
Part of a two-component system that dominates signal transduction in bacteria, the phosphate-juggling protein switch mapped out by Kern and her colleagues works by snatching a single phosphate ion from the amino acid histidine. The phosphorylated protein then binds to bacterial DNA, turning on genes such as those that instigate infection. These protein switches are ubiquitous in bacteria, but aren't found in humans -- making them an ideal target for antibiotics.
The protein switch studied by Kern is part of a common two-component system wherein a biological signal prompts a histidine molecule on one component to transfer a phosphate ion to an aspartate molecule on a second component. A strikingly similar two-component mechanism operates among many species of bacteria. "Our goal was to unravel the structural basis of the switch in the signal cascade at atomic resolution, with the hopes of developing new approaches for treating multiple-resistant infections," Kern says.
It's the first time the structure of such a short-lived protein has ever been pinpointed by scientists, Kern says, and heralds new possibilities for future NMR imaging of other evanescent biomolecules.
Key to the research was an innovative approach to nuclear magnetic resonance (NMR) spectroscopy that allowed Kern to regenerate, for a day and a half, the fleeting active configuration the protein switch normally assumes only during the few minutes when it grabs and holds a phosphate ion. The rapid loss of these ions -- necessary for fast responses to the environment -- usually makes the active, phosphate-bound form of the switch far too transient for structural analysis. To keep the protein switch in its active state long enough to get a good snapshot, Kern collected NMR spectra on the protein during catalysis using a constant stream of phosphate.
Kern's co-authors on the paper are Brian F. Volkman of the University of Wisconsin, Sydney Kustu of the University of California at Berkeley, and Peter Luginbühl, Michael J. Nohaile, and David E. Wemmer of the Lawrence Berkeley National Laboratory. The research was sponsored by the U.S. Department of Energy and the National Science Foundation.
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