Stephen G Sligar

Stephen G Sligar

s-sligar@illinois.edu

116A Morrill Hall
Office: (217) 244-9872
Lab: (217) 244-5329

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

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

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. Hormone biosynthetic cancer targets. Mechanisms of drug metabolism. Cancer signaling through the Ras pathways.

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 understanding the mechanisms of cancer signaling on the membrane surface.

Adrenergic G-protein coupled receptor

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

Representative Publications

379 Total Publications; Google Scholar h-index=100; 38,211 total citations

Ghazarian, H., Hu, W., Mao, A., Nguyen, T., Vaidehi, N., Sligar, S.G. and Shively, J.E. (2019) "NMR Analysis of Free and Lipid Nanodisc Anchored CEACAM1 Membrane Proximal Peptides with Ca(2+)/CaM" Biochem. Biophys. Acta Biomembranes 1861, 787-797.

Camp, T., McLean, M., Kato, M., Cheruzel, L. and Sligar, S. G. (2019) "The Hydrodynamic Motion of Nanodiscs" Physics and Chemistry of Lipids, 220, 28-35.

Denisov, I.G., Grinkova, Y., Nandigrami, P., Shekhar, M., Tajkhorshid, E. and Sligar, S.G. (2019) "Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213" Biochemistry, on line.

Wong, P., Li, L., Chea, J., Poku, E., Ebner, T. Bowkes, N., Wong, J. Y. C., Yazaki, P. J., Sligar, S. G., and Shively, J. E. (2019) “Antibody targeted PET Imaging of 64Cu-DOTA-Anti-CEA PEGylated Lipid Nanodiscs in CEA positive tumors” Biochem. Biophys. Acta Biomembranes in Press

Mustafa, G., Nandekar, P.P., Camp, T.J., Bruce, N.J., Gregory, M.C., Sligar, S.G. and Wade, R.C. (2019) “Influence of Transmembrane Helix Mutations on Cytochrome P450-Membrane Interactions and Function” Biophysical Journal 116, 1-14.

Bu, R.L., Clark, J., DiChiara, T., Sligar, S.G. and Klein, W.L. (2018) “SMPL Synaptic Membranes: Nanodisc-Mediated Synaptic Membrane Mimetics Expand the Toolkit for Drug Discovery and the Molecular Biology of the Synapses.” Springer Nature Neuromethods 141, Synaptosomes (Murphy, K. M., ed.) pp. 227-250.

Duggal, R., Denisov, I.G. and Sligar, S.G. (2018) “Cytochrome b5 Enhances Androgen Synthesis by Rapidly Reducing the CYP17A1 Oxy-complex in the Lyase Step” FEBS Letters 592, 2282-2288.

Mak, P.J., Duggal, R., Denisov, I.G., Gregory, M.C. and Sligar, S.G. (2018) “Human Cytochrome CYP17A1: The Structural Basis for Compromised Lyase Activity with 17-Hydroxyprogesterone” J. American Chemical Society 140, 7324-7331.

McLean, M. A., Gregory, M.C. and Sligar, S. G. (2018) "Nanodiscs: A Controlled Bilayer Surface for the study of Membrane Proteins" Annual Reviews Biophysics 47, 107-124.

Gregory, M.C., Mak, P.J., Khatri, Y., Kincaid, J.R. and Sligar, S.G. (2018) "Human CYP17A1: Control of Substrate Preference by Asparagine 202." Biochemistry 57, 764-771. PMC5801141.

Denisov, I.G., Baylon, J.L., Grinkova, Y.V., Tajkhorshid, E. and Sligar, S.G. (2018) "Drug-Drug Interactions Between Atorvastatin and Dronedarone Mediated by Monomeric CYP3A4" Biochemistry 57, 805-816. PMC5800941.

Mak, P. J. and Denisov, I. G. (Sligar lab) (2018) "Spectroscopic Studies of the Cytochrome P450 Reaction Mechanism." BBA Proteins and Proteomics 1866, 178-204.

Complete Publications List