The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

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 (www.nanodiscinc.com). 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. Our laboratory continues to participate in several federally funded programs of nanoscale science and technology that are centered on the Urbana Campus as well as at other academic institutions. Research support sources include the National Science Foundation, the National Institutes of Health and research agencies from other countries.

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

Representative Publications

Shaw, A.W., Pureza, V.S., Sligar, S.G., and Morrissey, J.H. 2007. The local phospholipid environment modulates the activation of blood clotting. J. Biological Chemistry, 282:6556–63. [Abstract]

Denisov, I.G., Baas, B.J., Grinkova, Y.V., and Sligar, S.G. 2007. Cooperativity in P450 CYP3A4: linkages in substrate binding, spin state, uncoupling and product formation. J. Biological Chemistry, 282:7066–76. [Abstract]

Nath, A., Atkins, W.M., and Sligar, S.G. 2007. Applications of phospholipid bilayer nanodiscs in the study of membranes and membrane proteins. Biochemistry, 46:2059–69. [Abstract]

Alami, M., Dalal, K., Lelj-Garolla, B., Sligar, S.G., and Duong, F. 2007. Nanodiscs unravel the interaction between the SecYEG channel and it's cytosolic partner SecA. The EMBO Journal, 1–10. [Abstract]

Bayburt, T.H., Leitz, A.J., Xie, G., Oprian, D.D., and Sligar, S.G. 2007. Transducin activation by nanoscale lipid bilayers containing one and two rhodopsins. J. Biol. Chem, 282:14875–81. [Abstract]

Sligar, S.G., and Denisov. I. G. 2007. Understanding cooperativity in human P450 mediated drug-drug interactions. Drug Metabolism Reviews, 39:1–13. [Abstract]

Shih, A.Y., Arkhipov, A., Freddolino, P.L., Sligar, S.G., and Schulten, K. 2007. Assembly of lipids and proteins into lipoprotein particles. J Phys Chem B, 38:11095–104. [Abstract]

Complete Publications List