The long range goal of this project is to study structure-function relationships in cytochromes P450 and related proteins using x-ray crystallography, molecular biology, and biochemistry. The focus will be on redox complexes formed between protein electron donors and acceptors in various P450 systems with an emphasis on three bacterial systems: P450cam, P450cin, and P450BM3. In addition to the traditional tools of crystallography, spectroscopy, protein engineering, and enzymology high field NMR will be employed to study protein-protein interactions.
This proposal centers on structure function relationships in cytochromes P450. P450s are one of the largest known enzyme families and participate in a vast array of biological processes. Especially important is the role played by P450s in drug metabolism, cancer, and the biosynthesis of critical steroid intermediates and antibiotics.
|Kaur, Parminder; Chamberlin, A Richard; Poulos, Thomas L et al. (2016) Structure-Based Inhibitor Design for Evaluation of a CYP3A4 Pharmacophore Model. J Med Chem 59:4210-20|
|Madrona, Yarrow; Hollingsworth, Scott A; Tripathi, Sarvind et al. (2014) Crystal structure of cindoxin, the P450cin redox partner. Biochemistry 53:1435-46|
|Sevrioukova, Irina F; Poulos, Thomas L (2014) Ritonavir analogues as a probe for deciphering the cytochrome P450 3A4 inhibitory mechanism. Curr Top Med Chem 14:1348-55|
|Poulos, Thomas L (2014) Heme enzyme structure and function. Chem Rev 114:3919-62|
|Poulos, Thomas L; Madrona, Yarrow (2013) Oxygen activation and redox partner binding in cytochromes P450. Biotechnol Appl Biochem 60:128-33|
|Batabyal, Dipanwita; Poulos, Thomas L (2013) Crystal structures and functional characterization of wild-type CYP101D1 and its active site mutants. Biochemistry 52:8898-906|
|Sevrioukova, Irina F; Poulos, Thomas L (2013) Pyridine-substituted desoxyritonavir is a more potent inhibitor of cytochrome P450 3A4 than ritonavir. J Med Chem 56:3733-41|
|Sevrioukova, Irina F; Poulos, Thomas L (2013) Dissecting cytochrome P450 3A4-ligand interactions using ritonavir analogues. Biochemistry 52:4474-81|
|Madrona, Yarrow; Hollingsworth, Scott A; Khan, Bushra et al. (2013) P450cin active site water: implications for substrate binding and solvent accessibility. Biochemistry 52:5039-50|
|Sevrioukova, Irina F; Poulos, Thomas L (2013) Understanding the mechanism of cytochrome P450 3A4: recent advances and remaining problems. Dalton Trans 42:3116-26|
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