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

Disease Research Interests

Cancer, Heart Disease, Stroke, and Thrombosis, Neurological and Behavioral Disorders

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.

A major goal of our laboratory is to understand the mechanisms involved in cancer signaling. In many cases, the relevant signaling complexes assemble on a membrane surface, yet the role of this critical component has not been investigated. We use the Nanodics system and extensive long-term molecular dynamics simulations to define the role of the membrane in determining the structure and interactions of the oncogenic protein KRas4b with the membrane surface and with its effector proteins. The Rat sarcoma (Ras) family of small membrane-associated GTPases are essential molecules involved in a signal transduction cascade that regulate, among other cellular properties, survival and proliferation. Central to Ras-mediated signal transduction is proper transport from the endoplasmic reticulum and subsequent stable association with the lipid bilayer of the plasma membrane where, once activated, Ras recruits downstream effector proteins leading to their subsequent activation.

A second major theme is the cytochrome P450 monosygenases involved in human drug metabolism and steroid hormone biosynthesis. The cytochromes P450 are members of a class of enzymes known oxygenases, as the incorporate an oxygen atom from atmospheric dioxygen into a substrate molecule. Our major efforts are focused on isolating and characterizing the reactive intermediates of the P450 catalytic cycle, the modes of molecular recognition of enzyme for its substrate and the details of inter-protein electron and proton transfer. For the drug metabolizing P450s, we seek to understand the molecular mechanisms of drug-drug interaction and the role of protein dynamics in linking the allosteric and catalytic sites of the enzymes. In the case of steroid biosynthesis, we are identifying the specific catalytic intermediate involved in catalysis with a goal of developing novel inhibitors of these enzymes that are central targets in the treatment of hormone dependent cancers.

Adrenergic G-protein coupled receptor

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

Awards

Christian B. Anfinsen Award, The Protein Society, 2020.

Sobor Award & Lectureship, American Society for Biochemistry and Molecular Biology, 2017.

Fellow, Academic Leadership, Committee on Institutional Cooperation
Fellow, Biophysical Society
Fellow, American Association for the Advancement of Science
Fellow, Jerome Karle Nobel Laureate World Innovation Foundation

NIH MIRA Award 2017-2026

Representative Publications

Over 400 Publications; Google Scholar h-index = 111; 46,630 total citations. Selected recent publications:

Liu, Y., Grinkova, Y., Gregory, M.C., Denisov, I.G. and Sligar, S.G. (2021) “Mechanism of the Clinically Relevant E305G Mutation in Human P450 CYP17A1” Biochemistry 60, 3262-3271

Denisov, I.G., Grinkova, Y.V., Camp, T., McLean, M.A. and Sligar, S.G. (2021) “Midazolam as a Probe for Drug-Drug Interactions Mediated by CYP3A4: Homotropic Allosteric Mechanism of Site-Specific Hydroxylation” Biochemistry 60, 1670-1681.

Liu, Y., Denisov, I.G., Sligar, S.G. and Kincaid, J.R. (2021) “Substrate-specific Allosteric Effects on the Enhancement of CYP17A1 Lyase Efficiency by Cytochrome b5” J. American Chemical Society 143, 3729-3733.

Sligar, S.G. and Denisov, I.G. (2020) “Nanodiscs: A Toolkit for Membrane Protein Science” Protein Science 30, 297-315.

Liu, Y., Denisov, I.G., Grinkova, Y.V., Sligar, S.G. and Kincaid, J.R. (2020) “P450 CYP17A1 Variant with a Disordered Proton Shuttle Assembly Retains Peroxo-Mediated Lyase Efficiency” Chemistry 26, 16846-16852.

Camp, T. and Sligar, S.G. (2020) “Nanodisc Self-Assembly is Thermodynamically Reversible and Controllable” Soft Matter 16, 5615-5623.

Gorfe, A. and Sligar, S.G. (2020) “Membrane Bound Ras as a Conformational Clock” Biophysical Journal 118, 1-3.

Camp, T., Mehta, K., Sligar, S.G. and Zhang, K. (2020) "Molecular Orientation Determination in Nanodiscs at the Single Molecule Level" Analytical Chemistry 92, 2229-2236.

McLean, M.A., Stephen, A.G. and Sligar, S.G. (2019) "PIP2 Influences the Conformational Dynamics of Membrane Bound KRAS4b" Biochemistry 58, 3537-3545.

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 58, 1411-1422.

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. (2020) “Antibody targeted PET Imaging of 64Cu-DOTA-Anti-CEA PEGylated Lipid Nanodiscs in CEA positive tumors” Bioconjugate Chemistry 31, 743-753.

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.

Complete Publications List