We seek to understand the mechanisms by which biological macromolecules recognize their partners in the formation of functional macromolecular assemblies that are critical to human health. Molecular recognition plays a central role in most, if not all, cellular processes. Failed recognition events have been implicated in numerous disease states, ranging from flawed control of long and short range signaling and cellular proliferation, to defects in important metabolic activities. Success in this endeavor will enable the discovery of new and better human therapeutics.
One Specific Aim centers on the cytochrome P450s involved in the human metabolism of drugs (CYP3A4, CYP2C8) and the biosynthesis of estrogens in normal and cancerous tissue (GYP19). CYP3A4 is the major P450 expressed in human liver and represents the main route for xenobiotic clearance, metabolizing approximately 50% of the Pharmaceuticals ingested by man. CYP2C8 plays an important role in the metabolism of a number of therapeutics, such as the anticancer drug taxol, antimalarials, anti-diabetics and the cholesterol lowering statins.
A second Aim focuses attention on the human G-protein coupled receptors (GPCRs). GPCRs account for a large fraction of marketed drugs designed to modulate homeostasis, including vision, smell, vascular tone, and neurosignaling. Initial work will focus on the B2adrenergic receptor that activates adenylyl cyclase through action of the stimulatory family of G-proteins upon catecholamine binding. This receptor is found in vascular and airway smooth muscle, functions in vaso- and broncho-dilation and is implicated in cardiovascular disease and asthma. Systematic investigations are proposed that focus on the major classes of recognition events in biological systems: Protein-protein recognition, defining the specificity and affinity of higher order oligomeric states that effect enzymatic metabolism and receptor signaling;Membrane recognition, understanding the role of the complex component mix (phospholipids, fatty acids, cholesterol) effecting receptor and enzyme activities;Protein- small molecule recognition, ascertaining multi-component interactions which regulate agonist, antagonist and reverse agonist effects and metabolic homo- and hetero-tropic cooperativity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033775-26
Application #
7744032
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Anderson, Vernon
Project Start
1984-12-01
Project End
2011-09-14
Budget Start
2009-12-01
Budget End
2011-09-14
Support Year
26
Fiscal Year
2010
Total Cost
$326,540
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Ye, Xin; McLean, Mark A; Sligar, Stephen G (2016) Phosphatidylinositol 4,5-Bisphosphate Modulates the Affinity of Talin-1 for Phospholipid Bilayers and Activates Its Autoinhibited Form. Biochemistry 55:5038-48
Denisov, Ilia G; Mak, Piotr J; Grinkova, Yelena V et al. (2016) The use of isomeric testosterone dimers to explore allosteric effects in substrate binding to cytochrome P450 CYP3A4. J Inorg Biochem 158:77-85
Reichart, Timothy M; Baksh, Michael M; Rhee, Jin-Kyu et al. (2016) Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding. Angew Chem Int Ed Engl 55:2688-92
Carney, Christiane E; Lenov, Ivan L; Baker, Catherine J et al. (2015) Nanodiscs as a Modular Platform for Multimodal MR-Optical Imaging. Bioconjug Chem 26:899-905
Denisov, Ilia G; Grinkova, Yelena V; Baylon, Javier L et al. (2015) Mechanism of drug-drug interactions mediated by human cytochrome P450 CYP3A4 monomer. Biochemistry 54:2227-39
Skar-Gislinge, Nicholas; Kynde, Søren A R; Denisov, Ilia G et al. (2015) Small-angle scattering determination of the shape and localization of human cytochrome P450 embedded in a phospholipid nanodisc environment. Acta Crystallogr D Biol Crystallogr 71:2412-21
Mak, Piotr J; Gregory, Michael C; Denisov, Ilia G et al. (2015) Unveiling the crucial intermediates in androgen production. Proc Natl Acad Sci U S A 112:15856-61
Wilcox, Kyle C; Marunde, Matthew R; Das, Aditi et al. (2015) Nanoscale Synaptic Membrane Mimetic Allows Unbiased High Throughput Screen That Targets Binding Sites for Alzheimer's-Associated A? Oligomers. PLoS One 10:e0125263
Marty, Michael T; Zhang, Hao; Cui, Weidong et al. (2014) Interpretation and deconvolution of nanodisc native mass spectra. J Am Soc Mass Spectrom 25:269-77
D'Antona, Aaron M; Xie, Guifu; Sligar, Stephen G et al. (2014) Assembly of an activated rhodopsin-transducin complex in nanoscale lipid bilayers. Biochemistry 53:127-34

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