Stephen G. Sligar
Director, School of Molecular and Cellular Biology
I.C. Gunsalus Professor of Biochemistry
Professor Sligar received his Ph.D from the University of Illinois in 1975. He did his undergraduate work at Drexel University. Professor Sligar has been a member of the faculty since 1982, and his research interests are in molecular biochemistry and biophysics.
Research
Our research efforts seek a precise understanding of the mechanisms of biological oxidation, the structure of collective assemblies of organized protein, lipid, and nucleic acid systems, the basis of molecular recognition in protein-protein and protein-nucleic acid complexes, and the detailed chemistry and physical operation of oxygenase and oxidase catalysis.
One research focus is on the cytochrome P450-dependent mixed-function oxidases that play central and crucial roles in mammalian, plant, insect, viral, and microbial metabolism. Central questions relating to the mechanisms of these enzymes include the precise chemistry involved in activating oxygen and substrate, and the identity of metal-oxygen-carbon intermediates in the catalytic event, the detailed physical description of inter- and intra-protein electron and proton transfer, and the structure of multi-enzyme membrane complexes involved in catalytic oxygenation and redox movement. We use low-temperature X-ray crystallography as well as cryoenzymology to trap intermediate states. We also are actively pursuing the problems of functional genomics in the large P450 superfamily. Through these efforts we have discovered multiple functions, not only in atmospheric dioxygen metabolism but also via reductive chemistries operating in totally anaerobic environmental niches. We also are investigating protoeomic issues related to thermal and baro-stability and related evolutionary connectivities of human metabolic profiles.
A second focus of our group uses the powerful tools of nanotechnology. As part of the NSF Nanoscale Science and Engineering Center, feedback controlled lithography and dip pen lithograph are being utilized to introduce controlled patterns onto surfaces from the single silicon atom level to the 100 nm scale. We are developing controlled self-assembly processes to generate mesoscale biological assemblies onto these patterned surfaces which can serve as sensors and high throughput screening arrays for pharmaceutical targets. Current efforts introduce single membrane proteins, such as G-protein coupled receptors and human and plant P450 isozymes, into controlled lipid rafts. Readout modalities include surface plasmon resonance, atomic force microscopy and photonic band gap architectures.
Publications
Kimmich, N., Das, A., Sevrioukova, I., Meharenna, Y., Sligar, S. G., and Poulos, T. L. (2007) "Electron Transfer Between Cytochrome P450CIN and It's FMN-Containing Redox Partner, Cindoxin." J. Biological Chemistry, 37, 27006-27011.
Denisov, I.G., Grinkova, Y.V., McLean, M.A., and Sligar, S. G. (2007) "The One Electron Autoxidatiaon of Human Cytochrome P4503A4." J. Biological Chemistry, 37, 26865-26873.
Sligar, S. G., and Denisov. I. G. (2007) "Understanding Cooperativity in Human P450 Mediated Drug-Drug Interactions." Drug Metabolism Reviews, 39, 1-13.
Hall, B., McLean, M. A., Davis, K., Casanova, J. E., Sligar, S. G., and Schwartz, M. A. (2008) "A Fluorescence Resonance Energy Transfer Activation Sensor for Arf6." Analytical Biochemistry, 374, 243-249.
Newcomb, M., Halgrimson, J.A., Horner, J.H., Wasinger, E.C., Chen, L.X., and Sligar, S.G. (2008) "X-Ray Absorption Spectroscopic Characterization of a Cytochrome P450 Compound II Derivative." Proceedings of the National Academy of Sciences, 24, 8179-8184.
Shih, A.Y., Sligar, S.G., and Schulten, K. (2008) "Molecular Models Need to be Tested: The Case of the Solar Flares Discoidal HDL Model." Biophysical Journal, 94, L87-L89.
Gruia, F., Ionascu, D., Kubo, M., Ye, X., Dawson, J., Osborne, R.L., Sligar, S.G., Denisov, I., Poulos, T.L., Terner, J., and Champion, P.M. (2008) "Low Frequency Dynamics of Caldariomyces fumago Chloroperoxidase Probed by Femtosecond Coherence Spectroscopy." Biochemistry, 47, 5156-5167.
Morrissey, J. H., Pureza, V., Davis-Harrison, R. L., Sligar, S. G., Ohkubo, Y. Z. and Tajkhorshid, E. (2008) "Blood Clotting Reactions on Nanoscale Phospholipid Bilayers." Thrombosis Research, 122 (Supplement 1), S23-S26.
Grinkova, Y.V., Denisov, I. G., Waterman, M. R.., Arase, M., Kagawa, N., and Sligar, S. G. (2008) "The Ferrous-Oxy Complex of Human Aromatase." Biochem Biophys Res Comm, 372, 379-382.
Kuhnel, K., Ke, N., Cryle, M. J., Sligar, S. G., Schuler, M. A., and Schlichting, I (2008) "Crystal Structures of Substrate-Free and Retinoic Acid-Bound Cyanobacterial Cytochrome P450 CYP120A1." Biochemistry, May 31, on-line.
Denisov, I. G., Mak, P. J., Makris, T. M., Sligar, S. G., and Kincaid, J. R. (2008) "Resonance Raman Characterization of the Peroxo and Hydroperoxo Intermediates in Cytochrome P450." Journal of Physical Chemistry A, 112, 13172-13179. PMID: 18630867.
Borch, J., Torta, F., Sligar, S. G., and Roepstorff, P. (2008) "Nanodiscs for Immobilization of Lipid Bilayers and Membrane Receptors: Kinetic Analysis of Cholera Toxin Binding to a Glycolipid Receptor." Analytical Chemistry, 80, 6245-6252. PMID: 18616345.
Zhao, J., Das, A., Schatz, G.C., Sligar, S.G., and VanDuyne, R. P. (2008) "Resonance Localized Surface Plasmon Spectroscoy: Sensing Substrate and Inhibitor Binding to Cytochrome P450." J. Phys. Chem, 112, 13084-13088. PMID: 16925400.
Goluch, E.D., Shaw, A. W., Sligar, S.G,, and Liu, C. (2008) "Microfluidic Patterning of Nanodisc Lipid Bilayers and Multiplexed Analysis of Protein Interaction." Lab Chip, 8, 1723-1728. PMID: 18813396.
Shih, A.Y., Freddolino, P.L., Arkhipov, A., Sligar, S.G., and Schulten, K. (2008) "Molecular Modeling of the Structural Properties and Formation of High-Density Lipoprotein Particles." Current Topics in Membranes, 60, 313-342.
Li, H., Das, A., Sibhatu, H., Jamal, J., Sligar, S.G., and Poulos, T.L. (2008) "Exploring the Electron Transfer Properties of Neuronal Nitric Oxide Synthase by Reversal of the FMN Redox Potential." J. Biol. Chem, 283, 34762-34772. PMID: 18852262.
Awards
- Fellow, Biophysical Society
- NSF Human Frontiers Science Program Research Award
- World Innovation Foundation Fellow
- NIH Merit Award
- Japan Society for the Promotion of Sciences Senior Fellow
- Bert L. and N. Kuggie Vallee Visiting Professor, Oxford University
- Fellow, AAAS
- UIUC University Scholar
- Fulbright Research Scholar, Institut de Biologie Physico-Chimique, Paris, and Yale University (1989-1990
