Stephen G Sligar

s-sligar@illinois.edu

116 Morrill Hall
Office: (217) 244-7395
Lab: (217) 244-5329
Fax: (217) 265-4073

Mail to: Molecular and Cellular Biology
116 Morrill Hall
505 S. Goodwin
Urbana, IL 61801
Lab Page
Curriculum Vita

Stephen G Sligar

Director of the School of Molecular and Cellular Biology
Professor of Biochemistry
Swanlund Endowed Chair
Professor of Chemistry
Professor of Biophysics and Computational Biology
Affiliate, Beckman Institute Molecular and Electronic Nanostructures theme

Research Topics

Drug Discovery, Endocrinology, Enzymology, Membrane Biology, Neurobiology, Protein Structure, Receptor Biochemistry, Signal Transduction

Education

B.S. 1970 Drexel University
Ph.D. 1975 University of Illinois, U-C
Postdoc. 1975-76 University of Illinois, U-C

Structural and functional characterization of macromolecular assemblies and the enzymes of biological oxidations, nanoscale systems for human therapeutics, genome/proteome analysis, macromolecular signaling and the biological details of cell migration.

The research efforts of the Sligar laboratory have several foci. A common thread is the development and utilization of novel technologies to understand the central mechanisms of biological function at the molecular and cellular level. A major effort is in the physical and chemical means by which enzymes catalyze biological oxidations. One research focus is on the cytochrome P450 dependent mixed function oxidases playing central and crucial roles in mammalian, plant, insect, viral, and microbial metabolism. Central questions relating to the mechanisms of these important biological oxidations include the precise chemistry involved in activation of 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. A second important research direction for our group is the development and execution of methodologies for and the determination of biological structures in the 5 nm - 500 nm 'mesoscale' size range. A major breakthrough in this arena continues to be the development of the Nanodisc system. Here chemical self-assembly is used to generate discoidal phospholipids bilayers, 6-20 nm in diameter, which are soluble in aqueous solution and can contain a variety of membrane protein targets. We have succeeded in incorporating a multitude of integral membrane proteins including many G-protein coupled receptors, various P450 monoxygenases and a variety of receptors and integrin assemblies. Most interesting is the fact that the incorporated membrane proteins are fully functional, including faithful reproduction of the complicated processes of trans membrane signaling. We use the Nanodisc system for both the discovery of new pharmacological agents as well as the therapeutic delivery of small molecule and protein based therapeutics.

Adrenergic G-protein coupled receptor

Adrenergic G-protein coupled receptor functionally solubilized by self-assembly into a 10 nm diameter Nanodisc.

Representative Publications

D'Antona A. M., Xie G., Sligar S. G., Oprian D. D. (2013) “Assembly of an Activated Rhodopsin/Transducin Complex in Nanoscale Lipid Bilayers”, Biochemistry. E. Pub

Mak P. J., Gregory, M. C., Sligar, S. G,. Kincaid, J. R. (2014) “Resonance Raman spectroscopy reveals that substrate structure selectively impacts the heme-bound diatomic ligands of CYP17.” Biochemistry, ASAP. doi: 10.1021/bi4014424. PMID: 24328388

Khatri, Y., Gregory, M. C., Grinkova, Y. V., Denisov, I. G., Sligar, S. G. (2014) “Active site proton delivery and the lyase activity of human CYP17A1.”, Biochem. Biophys. Res. Commun., 443(1), 179-184. PMID: 24299954

Gregory, M. C., Denisov, I. G., Grinkova, Y. G., Khatri, Y. and Sligar S. G. (2013) "Kinetic Solvent Isotope Effect in Human P450 CYP17A1-Mediated Androgen Formation: Evidence for a Reactive Peroxoanion Intermediate.", J. Am. Chem. Soc., 135 (44), 16245-16247. PMID: 24160919

Sun, Y., Zeng, W., Benabbas, A., Ye, X., Denisov, I., Sligar, S.G., Du, J., Dawson, J. H., and Champion, P. M. (2013) "Investigations of Heme Ligation and Ligand Switching in Cytochromes P450 and P420." Biochemistry, 52 (34), 5941-5951. PMID: 23905516

Vishnivetskiy, S. A., Ostermaier, M. K., Singhal, A., Panneels, V., Homan, K. T., Glukhova, A., Sligar, S.G., Tesmer, J. J., Schertler, G. F., Standfull, J., and Gurevich, V. V. (2013) "Constitutively Active Rhodopsin Mutants Causing Night Blindness are Effectively Phosphorylated by GRKs but Differ in Arrestin-1 Binding." Cell Signal. 25(11): 2155-2162. PMID: 23872075

Baylon, J. L., Lenov, I., Sligar, S. G., and Tajkhorshid, E. (2013) "Characterizing the Membrane-Bound State of Cytochrome P450 3A4: Structure, Depth of Insertion, and Orientation." J. Am. Chem. Soc. 135, 8542-8551. PMID: 23697766; PMCID: PMC3682445

Luthra, A., Gregory, M., Grinkova, Y. V., Denisov, I. G., Sligar, S. G. (2013) "Nanodiscs in the studies of membrane-bound cytochrome P450 enzymes." Methods Mol. Biol., 987, 115-127. PMID: 23475672

Numata, M., Grinkova, Y. V. , Mitchell, J. R. , Chu, Hong Wei, Sligar, S. G., Voelker D. R. (2013) "Nanodiscs as a therapeutic delivery agent: inhibition of respiratory syncytial virus infection in the lung." International Journal of Nanomedicine, 8, 1417-1427. PMID: 23717040

Gregory, M., Mak, P.J., Sligar, S. G., and Kincaid, J.R. (2013) “Differential Hydrogen Bonding in Human CYP17 Dictates Hydroxylation Versus Lyase Chemistry.” Angewandte Chemie, Int. Ed. 52, 5342-5345. PMID: 23576395

Sloan, C. D., Marty, M. T., Sligar, S. G., Bailey, R. C. (2013) "Interfacing lipid bilayer nanodiscs and silicon photonic sensor arrays for multiplexed protein-lipid and protein-membrane protein interaction screening." Anal. Chem., 85(5), 2970-2976. PMID: 23425255

Marty, M. T., Wilcox, K. C., Klein, W. L., Sligar, S. G. (2013) "Nanodisc-solubilized membrane protein library reflects the membrane proteome." Anal. Bioanal. Chem., 405, 4009-4016. PMID: 23400332

Schuler, M. A., Denisov, I. G., Sligar, S. G. (2013) "Nanodiscs as a new tool to examine lipid-protein interactions." Methods Mol Biol. 974, 415-433. PMID: 23404286

Complete Publications List