Crystal structure of the FMN‐binding domain of human cytochrome P450 reductase at 1.93 Å resolution
Open Access
- 1 January 1999
- journal article
- research article
- Published by Wiley in Protein Science
- Vol. 8 (2), 298-306
- https://doi.org/10.1110/ps.8.2.298
Abstract
The crystal structure of the FMN‐binding domain of human NADPH‐cytochrome P450 reductase (P450R‐FMN), a key component in the cytochrome P450 monooxygenase system, has been determined to 1.93 å resolution and shown to be very similar both to the global fold in solution (Barsukov I et al., 1997, J Biomol NMR 10:63–75) and to the corresponding domain in the 2.6 å crystal structure of intact rat P450R (Wang M et al., 1997, Proc Nat Acad Sci USA 94:8411–8416). The crystal structure of P450R‐FMN reported here confirms the overall similarity of its α‐β‐α architecture to that of the bacterial flavodoxins, but reveals differences in the position, number, and length of the helices relative to the central β‐sheet. The marked similarity between P450R‐FMN and flavodoxins in the interactions between the FMN and the protein, indicate a striking evolutionary conservation of the FMN binding site. The P450R‐FMN molecule has an unusual surface charge distribution, leading to a very strong dipole, which may be involved in docking cytochrome P450 into place for electron transfer near the FMN. Several acidic residues near the FMN are identified by mutagenesis experiments to be important for electron transfer to P450 2D6 and to cytochrome c, a clear indication of the part of the molecular surface that is likely to be involved in substrate binding. Somewhat different parts are found to be involved in binding cytochrome P450 and cytochrome c.Keywords
This publication has 36 references indexed in Scilit:
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine as a Substrate of Cytochrome P450 2D6: Allosteric Effects of NADPH−Cytochrome P450 ReductaseBiochemistry, 1997
- Crystallization and Preliminary X-Ray Diffraction Studies of Human Cytochrome P450 ReductaseJournal of Structural Biology, 1996
- Crystal Structure of Hemoprotein Domain of P450BM-3, a Prototype for Microsomal P450'sScience, 1993
- Structure of the oxidized long‐chain flavodoxin from anabaena 7120 at 2 å resolutionProtein Science, 1992
- Comparison of the crystal structures of a flavodoxin in its three oxidation states at cryogenic temperaturesJournal of Molecular Biology, 1991
- Improved methods for building protein models in electron density maps and the location of errors in these modelsActa Crystallographica Section A Foundations of Crystallography, 1991
- An unusual yet strongly conserved flavoprotein reductase in bacteria and mammalsTrends in Biochemical Sciences, 1991
- Structure of oxidized flavodoxin from Anacystis nidulansJournal of Molecular Biology, 1983
- Properties of hepatic reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductaseBiochemistry, 1973