Three-dimensional structure of NADPH–cytochrome P450 reductase: Prototype for FMN- and FAD-containing enzymes

Proceedings of the National Academy of Sciences of the United States of America - Tập 94 Số 16 - Trang 8411-8416 - 1997
Ming Wang1, David L. Roberts1, Rosemary Paschke1, Thomas M. Shea1, Bettie Sue Siler Masters1, Jung-Ja P. Kim1
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226; and Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78284

Tóm tắt

Microsomal NADPH–cytochrome P450 reductase (CPR) is one of only two mammalian enzymes known to contain both FAD and FMN, the other being nitric-oxide synthase. CPR is a membrane-bound protein and catalyzes electron transfer from NADPH to all known microsomal cytochromes P450. The structure of rat liver CPR, expressed in Escherichia coli and solubilized by limited trypsinolysis, has been determined by x-ray crystallography at 2.6 Å resolution. The molecule is composed of four structural domains: (from the N- to C- termini) the FMN-binding domain, the connecting domain, and the FAD- and NADPH-binding domains. The FMN-binding domain is similar to the structure of flavodoxin, whereas the two C-terminal dinucleotide-binding domains are similar to those of ferredoxin–NADP + reductase (FNR). The connecting domain, situated between the FMN-binding and FNR-like domains, is responsible for the relative orientation of the other domains, ensuring the proper alignment of the two flavins necessary for efficient electron transfer. The two flavin isoalloxazine rings are juxtaposed, with the closest distance between them being about 4 Å. The bowl-shaped surface near the FMN-binding site is likely the docking site of cytochrome c and the physiological redox partners, including cytochromes P450 and b 5 and heme oxygenase.

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Tài liệu tham khảo

A L Shen, C B Kasper Handbook of Experimental Pharmacology, eds J B Schenkman, H Greim (Springer, New York), pp. 35–59 (1993).

10.1007/978-1-4757-2391-5_7

10.1016/S0021-9258(18)93967-0

10.1016/S0021-9258(19)73803-4

10.1016/S0021-9258(19)45183-1

10.1016/S0021-9258(19)86797-2

10.1016/S0021-9258(19)51185-1

10.1021/bi00705a023

10.1016/S0021-9258(17)34250-3

10.1016/S0021-9258(18)97152-8

10.1016/S0021-9258(19)57385-9

10.1016/S0021-9258(18)62453-6

10.1021/bi00355a036

10.1073/pnas.91.18.8710

10.1006/abbi.1995.1037

10.1021/bi00736a018

10.1016/S0021-9258(18)50289-1

W E Blumberg, Y Nisimoto, H S Mason Oxygenases and Oxygen Metabolism, eds M Nozake, S Yamamoto, Y Ishimura, M J Coon, L Ernster, R W Estabrook (Academic, New York), pp. 333–343 (1982).

10.1021/bi00447a022

10.1111/j.1432-1033.1990.tb15606.x

10.1021/bi00132a009

10.1021/bi00333a031

10.1016/S0021-9258(18)83274-4

10.1073/pnas.92.8.3214

10.1016/0022-2836(68)90205-2

10.1107/S0108767383001592

W Furey phases Manual (Veterans Administration Medical Center, Pittsburgh, PA, 1995).

10.1016/0076-6879(85)15009-3

C Cambillau, A Roussel turbo-frodo: Manual for a Molecular Graphics Program for Silicon Graphics (Silicon Graphics, Mountain View, CA, , Version 5.4. (1993).

10.1107/S0108767386099622

A T Brunger x-plor: A System for X-ray Crystallography and NMR, (Yale Univ. Press, New Haven, CT, , Version 3.1. (1992).

10.1107/S0021889891004399

10.1107/S0907444994006396

10.1073/pnas.70.12.3857

10.1126/science.1986412

10.1021/bi00009a004

10.1006/jmbi.1995.0273

10.1021/bi00412a038

10.1006/jmbi.1994.0127

10.1126/science.1280857

10.1016/S0021-9258(18)46999-2

10.1006/abbi.1996.0395

10.1016/0022-2836(85)90297-9

A Nichols grasp: Graphical Representation and Analysis of Surface Properties (Columbia Univ., New York, 1992).

10.1016/S0021-9258(18)67009-7

10.1074/jbc.270.46.27475

J R Gillette, B B Brodie, B N La Du J Pharmacol Exp Ther 119, 532–541 (1957).

10.1016/0014-5793(92)80452-M

10.1038/351714a0

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Proceedings of the National Academy of Sciences of the United States of America

Tập 94 Số 16

8411-8416

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