Thomas L. Selby
Structure-Function Studies for Enzyme Inhibitor and Biosensor Design

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Assistant Professor, Department of Chemistry Ph.D., The Ohio State University Phone: 407-823-6752 E-mail: tselby@mail.ucf.edu View Full Curriculum Vita

July, 2005: Otto Phanstiel (PI), Thomas Selby and Martin Richardson were awarded funding from Mannkind Biopharmaceuticals to study proprietary drug delivery technologies ($184,551).

Research
Our lab advances pure and applied structure-function studies of enzymes for the design of inhibitors and biosensors used in the treatment of cancer and metabolic diseases. Phosphatidylinositol-specific phospholipases C (PI-PLC) are key effectors of the action of growth factors, neurotransmitters, and hormones. Using bacterial PI-PLCs-which are an excellent model to use to begin to understand the more complex mammalian enzymes-our goal is to understand the relationship between the catalytic mechanism of the whole family of PI-PLCs using x-ray crystallography, computational inhibitor design, and enzyme inhibition studies. Our recent x-ray structure of the BtPI-PLC (PDB ID Code: 1T6M) is the first bacterial enzyme determined that utilizes a calcium ion. A second calcium dependent PI-PLC enzyme from S. antibioticus is also being completed to allow novel inhibitors to be designed for use in various medical applications.

Novel proteases involved in cellular signaling are also being investigated to determine a) the high resolution crystal structure(s) of the enzyme(s), b) the substrate specificity of each protease, c) the related cellular signaling receptor(s) and d) the overall signaling pathway(s). Once determined this information will permit a number of therapies to be designed against previously unknown cellular signaling pathways for cancer and metabolic disease therapies. Due to protease domains representing a large fraction of the human genome and being involved in a number of disease states, we are developing high throughput computational methodologies to speed up the process of substrate determination and receptor identification.

Biological nanotechnology in metabolic monitoring is also being pursed using oxidation reduction (REDOX) enzymes. By arraying these enzymes on a chip, a nanoscale biosensor that can distinguish different molecules in a mixture can be developed based on each enzyme's substrate specificity. Such devices will enable certain types of disease "signatures" to be determined and allow rapid analysis of biological samples for accurate detection of metabolic disorders.

Inositol Signaling Project Mammalian phosphatidylinositol-specific phospholipases C (PI-PLC) are key effectors of the action of growth factors, neurotransmitters, and hormones.

Selected Publications

1. Heine A, Canaves JM, von Delft F, et al. Crystal structure of O-acetylserine sulfhydrylase (TM0665) from Thermotoga maritima at 1.8 A resolution. Proteins-Structure Function and Bioinformatics 2004;56(2):387-91.

2. Selby T and Stevens R, Bioinformatics and high-throughput protein production for structural genomics. T.L. Selby, R.C. Stevens Gene Cloning and Expression Technologies, Weiner and Lu editors, Eaton Publishing, (2004).

3. Schwarzenbacher R, von Delft F, Canaves JM, et al. Crystal structure of an iron-containing 1,3-propanediol dehydrogenase (TM0920) from Thermotoga maritima at 1.3 angstrom resolution. Proteins-Structure Function and Genetics 2004;54(1):174-7.

4. Weselak M, Patch MG, Selby TL, Knebel G, Stevens RC. Robotics for automated crystal formation and analysis. In: Macromolecular Crystallography, Pt C; 2003:45-76.

5. Yuan CH, Selby TL, Li JA, Byeon IJL, Tsai MD. Tumor suppressor INK4: Refinement of p16(INK4A) structure and determination of p15(INK4B) structure by comparative modeling and NMR data. Protein Science 2000;9(6):1120-8.

Graduate Students
Students in my lab are trained in various techniques ranging from molecular biology and protein expression to high resolution x-ray structure determination and inhibitor design. Students who have worked on these projects have found employment at various academic institutions, NASA, and the pharmaceutical industry.