Institute of Molecular Biology


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Research Interests

Our group uses an interdisciplinary approach in applying physical techniques to the study of biological molecules, especially the structure, function, and interaction of enzymes, chemoreceptors and fluorescent proteins. The primary techniques we use are mutagenesis, x-ray crystallography and spectroscopy, but occasionally we perform computer modeling of enzyme active sites and other properties of proteins. In the laboratory, chemists and biologists collaborate with physicists to achieve a broader intellectual basis for the research.

Bacterial Chemoreceptor Proteins

In collaboration with Karen Guillemin’s group, we are interested to understand the structure and function of sensory proteins that allow the bacterium Helicobacter pylori to thrive within the hostile environment of the human stomach. Crystal structures were determined for TlpA and TlpB, two of the three critical chemotaxis receptors. Much subsequent work has, for the first time, led to a rather complete understanding of how a receptor (TlpB, see illustration) can sense pH, allowing the bacteria to navigate away from the low-pH interior of the stomach to the lining, where they can induce inflammation, ulcers and even cancerous transformations. Studies of TlpA, TlpB and TlpD are ongoing in both laboratories.

Green Fluorescent Protein

Since 1996 we have worked with Green Fluorescent Protein, which spontaneously rearranges itself to become fluorescent, absorbing blue light and re-emitting green light. GFP and its red, yellow and blue cousins are enormously popular as visible tag for proteins of interest or as a marker for gene expression. Using structure-based genetic engineering techniques we successfully constructed visual pH indicators, halide (chloride) concentration indicators and sensors that report on the thiol/disulfide redox potential within cells. Furthermore, the color of the protein can be modified by changing the environment or internal structure of the chromophore, which is derived from the primary sequence (Xaa)65-Tyr66-Gly67. Crystal structures were determined of related fluorescent proteins from corals that fluoresce yellow, orange and red, enabling multicolor reporting of a variety of cellular processes. It is fascinating that these different fluorescent proteins are nevertheless based on the same Xaa-Tyr-Gly peptide.

Enzyme Structure-Function Relationships

For many years we worked to determine structure function relationships in citrate synthase, which is the entry to the citric acid cycle and is found in every organism examined. Citrate synthase, in its rate-determining step, abstracts a proton from the methyl group of acetylCoenzyme A to form a carbon-carbon double bond. The side chain which accomplishes this task is Asp375 working in concert with His274 (sequence numbering of pig heart enzyme). This equilibrium for this seemingly simple reaction is disfavored in solution by 12-15 orders of magnitude, and proposals for how an enzyme can do this remain extremely controversial. Recently, we determined the crystal structure of malate synthase, an enzyme that catalyzes an essentially identical reaction. These enzymes are completely unrelated in sequence and structure, the underlying chemistry is essentially the same, but all of the details with the exception of an aspartic acid acting as a base are different. Evidently, Nature has discovered only one solution to this fundamental problem in chemistry, but the machinery is almost totally different!

research How TlpB senses acidic pH: The TlpB receptor (left) binds a molecule of urea (right), which requires that Asp114 be negatively charged. At pH below 4, Asp114 becomes neutralized, which interferes with urea binding. This in turn causes major structural changes in the receptor, which are communicated through the transmembrane stalk to interior components. Ultimately, the bacteria respond by swimming away from low pH (acidic) environments, toward the stomach lining where they can cause great damage.

Recent publications

(pulled from pubmed)