Abstract

The kinetics of CO binding to P450 were analyzed using the Maximum Entropy Method. This analysis yields kinetic distribution profiles that correspond to P450 conformational landscapes. The results show that P450 1A1 and 3A4 structures are best defined as distributions of two or three conformers. Addition of substrate modified the distributions. In contrast, a flexible conformation was observed for the alcohol inducible and carcinogen metabolizing P450 2E1. The results suggest that the conformation of this P450 switches during the catalytic cycle, allowing for oxidative uncoupling and production of reactive oxygen species.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005318-24
Application #
7337844
Study Section
(CCRN)
Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2006
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Michl, Josef; Scharf, Bruce; Schmidt, Anna et al. (2006) PNC-28, a p53-derived peptide that is cytotoxic to cancer cells, blocks pancreatic cancer cell growth in vivo. Int J Cancer 119:1577-85
Duncan, Thomas; Chen, James M; Friedman, Fred K et al. (2004) Comparison of molecular dynamics averaged structures for complexes of normal and oncogenic ras-p21 with SOS nucleotide exchange protein, containing computed conformations for three crystallographically undefined domains, suggests a potential role of these Protein J 23:217-28
Chie, Lyndon; Adler, Victor; Friedman, Fred K et al. (2004) An effector peptide from glutathione-S-transferase-pi strongly and selectively blocks mitotic signaling by oncogenic ras-p21. Protein J 23:235-8
Chie, Lyndon; Friedman, Fred K; Duncan, Thomas et al. (2004) Loop domain peptides from the SOS ras-guanine nucleotide exchange protein, identified from molecular dynamics calculations, strongly inhibit ras signaling. Protein J 23:229-34
Friedman, Fred K; Robinson, Richard C; Dai, Renke (2004) Molecular modeling of mammalian cytochrome P450s. Front Biosci 9:2796-806
Bustin, Michael; Robinson, Richard C; Friedman, Fred K (2004) Immunochemical analysis of chromatin. Methods Enzymol 376:209-20
Dai, R; Pincus, M R; Friedman, F K (2000) Molecular modeling of mammalian cytochrome P450s. Cell Mol Life Sci 57:487-99
Smith, S V; Koley, A P; Dai, R et al. (2000) Conformational modulation of human cytochrome P450 2E1 by ethanol and other substrates: a CO flash photolysis study. Biochemistry 39:5731-7
Omata, Y; Dai, R; Smith, S V et al. (2000) Synthetic peptide mimics of a predicted topographical interaction surface: the cytochrome P450 2B1 recognition domain for NADPH-cytochrome P450 reductase. J Protein Chem 19:23-32
Wei, X; Dai, R; Zhai, S et al. (1999) Inhibition of human liver cytochrome P-450 1A2 by the class IB antiarrhythmics mexiletine, lidocaine, and tocainide. J Pharmacol Exp Ther 289:853-8