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PDBsum entry 1amo

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1amo
Jmol
Contents
Protein chains
601 a.a. *
Ligands
FAD ×2
FMN ×2
NAP ×2
Waters ×156
* Residue conservation analysis
PDB id:
1amo
Name: Oxidoreductase
Title: Three-dimensional structure of NADPH-cytochrome p450 reductase: prototype for fmn-and fad-containing enzymes
Structure: NADPH-cytochrome p450 reductase. Chain: a, b. Fragment: hydrophilic domain. Synonym: cpr, p450r. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Organ: liver. Cellular_location: mitochondria. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.60Å     R-factor:   0.200     R-free:   0.310
Authors: M.Wang,D.L.Roberts,R.Paschke,T.M.Shea,B.S.S.Masters, J.J.P.Kim
Key ref:
M.Wang et al. (1997). Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes. Proc Natl Acad Sci U S A, 94, 8411-8416. PubMed id: 9237990 DOI: 10.1073/pnas.94.16.8411
Date:
17-Jun-97     Release date:   17-Jun-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00388  (NCPR_RAT) -  NADPH--cytochrome P450 reductase
Seq:
Struc:
 
Seq:
Struc:
678 a.a.
601 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.6.2.4  - NADPH--hemoprotein reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: NADPH + n oxidized hemoprotein = NADP+ + n reduced hemoprotein
NADPH
+ n oxidized hemoprotein
= NADP(+)
+ n reduced hemoprotein
      Cofactor: FAD; FMN
FAD
Bound ligand (Het Group name = FAD) corresponds exactly
FMN
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   6 terms 
  Biological process     regulation of growth plate cartilage chondrocyte proliferation   24 terms 
  Biochemical function     electron carrier activity     13 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.94.16.8411 Proc Natl Acad Sci U S A 94:8411-8416 (1997)
PubMed id: 9237990  
 
 
Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes.
M.Wang, D.L.Roberts, R.Paschke, T.M.Shea, B.S.Masters, J.J.Kim.
 
  ABSTRACT  
 
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 A 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 A. 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 b5 and heme oxygenase.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Stereoview of the electron density in the vicinity of the FAD and FMN of CPR. The 3|F[o]| 2|F[c]| electron density map computed^ with 2.6 Å resolution data is contoured at 1.2 level. Residues within close contact of the flavin ring are labeled. Four aromatic^ residues sandwich the flavin rings: Y178 and Y140 for FMN and^ Y456 and W677 for FAD.
Figure 4.
Fig. 4. Stereoview of the cofactor arrangement in CPR and multiple conformers for the bound NADP+. Electrons flow from NADPH to FAD and then to FMN. The FMN and^ FAD are represented by ball-and-stick, with the xylene portions of the isoalloxazine rings oriented toward each other. The adenine^ portion of NADP+ binds in a single conformation (ball-and-stick) while the nicotinamide^ (stick only) binds in multiple conformations. By rotation about the P[N]---O---P[A] bond, the nicotinamide ring could displace W677 at the re-side of the FAD ring, placing it in the optimum orientation for hydride transfer from the NADPH to the N5 position of the^ FAD cofactor.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

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19398561 B.S.Masters, and B.S.Masters (2009).
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Regulation of interdomain interactions by calmodulin in inducible nitric-oxide synthase.
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18982412 D.Eberle, P.Ullmann, D.Werck-Reichhart, and M.Petersen (2009).
cDNA cloning and functional characterisation of CYP98A14 and NADPH:cytochrome P450 reductase from Coleus blumei involved in rosmarinic acid biosynthesis.
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Internal electron transfer in multi-site redox enzymes is accessed by laser excitation of thiouredopyrene-3,6,8-trisulfonate (TUPS).
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19243433 K.R.Wolthers, and N.S.Scrutton (2009).
Cobalamin uptake and reactivation occurs through specific protein interactions in the methionine synthase-methionine synthase reductase complex.
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Cloning, purification, crystallization and preliminary X-ray analysis of a chimeric NADPH-cytochrome P450 reductase.
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PDB code: 3fjo
19432415 M.Kasim, H.C.Chen, and R.P.Swenson (2009).
Functional characterization of the re-face loop spanning residues 536-541 and its interactions with the cofactor in the flavin mononucleotide-binding domain of flavocytochrome P450 from Bacillus megaterium.
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19583765 M.Medina (2009).
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Androgen synthesis in adrenarche.
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19250198 Y.Hong, H.Li, Y.C.Yuan, and S.Chen (2009).
Molecular characterization of aromatase.
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18218133 D.C.Gonzalez-Kristeller, L.Farage, L.C.Fiorini, W.F.Loomis, and A.M.da Silva (2008).
The P450 oxidoreductase, RedA, controls development beyond the mound stage in Dictyostelium discoideum.
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18852262 H.Li, A.Das, H.Sibhatu, J.Jamal, S.G.Sligar, and T.L.Poulos (2008).
Exploring the electron transfer properties of neuronal nitric-oxide synthase by reversal of the FMN redox potential.
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18513324 H.Sumimoto (2008).
Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species.
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18815130 J.Tejero, A.Biswas, Z.Q.Wang, R.C.Page, M.M.Haque, C.Hemann, J.L.Zweier, S.Misra, and D.J.Stuehr (2008).
Stabilization and characterization of a heme-oxy reaction intermediate in inducible nitric-oxide synthase.
  J Biol Chem, 283, 33498-33507.
PDB code: 3dwj
18279389 M.A.Musumeci, A.K.Arakaki, D.V.Rial, D.L.Catalano-Dupuy, and E.A.Ceccarelli (2008).
Modulation of the enzymatic efficiency of ferredoxin-NADP(H) reductase by the amino acid volume around the catalytic site.
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18260112 M.Medina, R.Abagyan, C.Gómez-Moreno, and J.Fernandez-Recio (2008).
Docking analysis of transient complexes: interaction of ferredoxin-NADP+ reductase with ferredoxin and flavodoxin.
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18847185 M.P.Hay, K.O.Hicks, K.Pchalek, H.H.Lee, A.Blaser, F.B.Pruijn, R.F.Anderson, S.S.Shinde, W.R.Wilson, and W.A.Denny (2008).
Tricyclic [1,2,4]triazine 1,4-dioxides as hypoxia selective cytotoxins.
  J Med Chem, 51, 6853-6865.  
18230729 N.Huang, V.Agrawal, K.M.Giacomini, and W.L.Miller (2008).
Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations.
  Proc Natl Acad Sci U S A, 105, 1733-1738.  
18556005 R.Nicoli, M.Bartolini, S.Rudaz, V.Andrisano, and J.L.Veuthey (2008).
Development of immobilized enzyme reactors based on human recombinant cytochrome P450 enzymes for phase I drug metabolism studies.
  J Chromatogr A, 1206, 2.  
18216718 S.N.Hart, S.Wang, K.Nakamoto, C.Wesselman, Y.Li, and X.B.Zhong (2008).
Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism.
  Pharmacogenet Genomics, 18, 11-24.  
18433346 S.N.Hart, and X.B.Zhong (2008).
P450 oxidoreductase: genetic polymorphisms and implications for drug metabolism and toxicity.
  Expert Opin Drug Metab Toxicol, 4, 439-452.  
18539133 S.Sarapusit, C.Xia, I.Misra, P.Rongnoparut, and J.J.Kim (2008).
NADPH-cytochrome P450 oxidoreductase from the mosquito Anopheles minimus: kinetic studies and the influence of Leu86 and Leu219 on cofactor binding and protein stability.
  Arch Biochem Biophys, 477, 53-59.  
18551037 V.Agrawal, N.Huang, and W.L.Miller (2008).
Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19.
  Pharmacogenet Genomics, 18, 569-576.  
18194664 Y.Higashimoto, M.Sugishima, H.Sato, H.Sakamoto, K.Fukuyama, G.Palmer, and M.Noguchi (2008).
Mass spectrometric identification of lysine residues of heme oxygenase-1 that are involved in its interaction with NADPH-cytochrome P450 reductase.
  Biochem Biophys Res Commun, 367, 852-858.  
17448174 B.S.Kim, S.Y.Kim, J.Park, W.Park, K.Y.Hwang, Y.J.Yoon, W.K.Oh, B.Y.Kim, and J.S.Ahn (2007).
Sequence-based screening for self-sufficient P450 monooxygenase from a metagenome library.
  J Appl Microbiol, 102, 1392-1400.  
17635179 C.E.Flück, C.Nicolo, and A.V.Pandey (2007).
Clinical, structural and functional implications of mutations and polymorphisms in human NADPH P450 oxidoreductase.
  Fundam Clin Pharmacol, 21, 399-410.  
17554763 C.Gherasim, D.S.Rosenblatt, and R.Banerjee (2007).
Polymorphic background of methionine synthase reductase modulates the phenotype of a disease-causing mutation.
  Hum Mutat, 28, 1028-1033.  
17598560 D.Kaewpa, S.Boonsuepsakul, and P.Rongnoparut (2007).
Functional expression of mosquito NADPH-cytochrome P450 reductase in Escherichia coli.
  J Econ Entomol, 100, 946-953.  
17174478 J.J.Perry, L.Fan, and J.A.Tainer (2007).
Developing master keys to brain pathology, cancer and aging from the structural biology of proteins controlling reactive oxygen species and DNA repair.
  Neuroscience, 145, 1280-1299.  
17288554 K.R.Wolthers, H.S.Toogood, T.A.Jowitt, K.R.Marshall, D.Leys, and N.S.Scrutton (2007).
Crystal structure and solution characterization of the activation domain of human methionine synthase.
  FEBS J, 274, 738-750.
PDB code: 2o2k
17534530 M.Unno, T.Matsui, and M.Ikeda-Saito (2007).
Structure and catalytic mechanism of heme oxygenase.
  Nat Prod Rep, 24, 553-570.  
17827787 S.N.Hart, Y.Li, K.Nakamoto, C.Wesselman, and X.B.Zhong (2007).
Novel SNPs in cytochrome P450 oxidoreductase.
  Drug Metab Pharmacokinet, 22, 322-326.  
17960482 W.Arlt (2007).
P450 oxidoreductase deficiency and Antley-Bixler syndrome.
  Rev Endocr Metab Disord, 8, 301-307.  
16915000 C.E.Flück, and W.L.Miller (2006).
P450 oxidoreductase deficiency: a new form of congenital adrenal hyperplasia.
  Curr Opin Pediatr, 18, 435-441.  
16407065 D.C.Lamb, Y.Kim, L.V.Yermalitskaya, V.N.Yermalitsky, G.I.Lepesheva, S.L.Kelly, M.R.Waterman, and L.M.Podust (2006).
A second FMN binding site in yeast NADPH-cytochrome P450 reductase suggests a mechanism of electron transfer by diflavin reductases.
  Structure, 14, 51-61.
PDB codes: 2bf4 2bn4
16900491 R.A.Brown, and D.A.Case (2006).
Second derivatives in generalized Born theory.
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16605249 R.Pejchal, E.Campbell, B.D.Guenther, B.W.Lennon, R.G.Matthews, and M.L.Ludwig (2006).
Structural perturbations in the Ala --> Val polymorphism of methylenetetrahydrofolate reductase: how binding of folates may protect against inactivation.
  Biochemistry, 45, 4808-4818.
PDB codes: 2fmn 2fmo
16234920 H.E.Seward, H.M.Girvan, and A.W.Munro (2005).
Cytochrome P450s: creating novel ligand sets.
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16249336 M.Jáchymová, P.Martásek, S.Panda, L.J.Roman, M.Panda, T.M.Shea, Y.Ishimura, J.J.Kim, and B.S.Masters (2005).
Recruitment of governing elements for electron transfer in the nitric oxide synthase family.
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15832443 M.J.Coon (2005).
Cytochrome P450: nature's most versatile biological catalyst.
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15793702 N.Huang, A.V.Pandey, V.Agrawal, W.Reardon, P.D.Lapunzina, D.Mowat, E.W.Jabs, G.Van Vliet, J.Sack, C.E.Flück, and W.L.Miller (2005).
Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
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15789405 T.Mayoral, M.Martínez-Júlvez, I.Pérez-Dorado, J.Sanz-Aparicio, C.Gómez-Moreno, M.Medina, and J.A.Hermoso (2005).
Structural analysis of interactions for complex formation between Ferredoxin-NADP+ reductase and its protein partners.
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PDB codes: 1e62 1e63 1e64 1go2 1qgy
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P450 oxidoreductase deficiency: a new disorder of steroidogenesis.
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15182370 A.J.Dunford, K.R.Marshall, A.W.Munro, and N.S.Scrutton (2004).
Thermodynamic and kinetic analysis of the isolated FAD domain of rat neuronal nitric oxide synthase altered in the region of the FAD shielding residue Phe1395.
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14758361 C.E.Flück, T.Tajima, A.V.Pandey, W.Arlt, K.Okuhara, C.F.Verge, E.W.Jabs, B.B.Mendonça, K.Fujieda, and W.L.Miller (2004).
Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.
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15264278 M.Adachi, K.Tachibana, Y.Asakura, T.Yamamoto, K.Hanaki, and A.Oka (2004).
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15009198 M.H.Hefti, K.J.Françoijs, S.C.de Vries, R.Dixon, and J.Vervoort (2004).
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Crystal structure of heme oxygenase-1 from cyanobacterium Synechocystis sp. PCC 6803 in complex with heme.
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PDB code: 1we1
14996812 S.J.Barkley, R.M.Cornish, and C.D.Poulter (2004).
Identification of an Archaeal type II isopentenyl diphosphate isomerase in methanothermobacter thermautotrophicus.
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15220035 W.Arlt, E.A.Walker, N.Draper, H.E.Ivison, J.P.Ride, F.Hammer, S.M.Chalder, M.Borucka-Mankiewicz, B.P.Hauffa, E.M.Malunowicz, P.M.Stewart, and C.H.Shackleton (2004).
Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.
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15350602 W.L.Miller (2004).
P450 oxidoreductase deficiency: a new disorder of steroidogenesis with multiple clinical manifestations.
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12787027 A.Gutierrez, A.W.Munro, A.Grunau, C.R.Wolf, N.S.Scrutton, and G.C.Roberts (2003).
Interflavin electron transfer in human cytochrome P450 reductase is enhanced by coenzyme binding. Relaxation kinetic studies with coenzyme analogues.
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14502987 L.Lamattina, C.García-Mata, M.Graziano, and G.Pagnussat (2003).
Nitric oxide: the versatility of an extensive signal molecule.
  Annu Rev Plant Biol, 54, 109-136.  
12709048 N.Carrillo, and E.A.Ceccarelli (2003).
Open questions in ferredoxin-NADP+ reductase catalytic mechanism.
  Eur J Biochem, 270, 1900-1915.  
12631275 R.D.Finn, J.Basran, O.Roitel, C.R.Wolf, A.W.Munro, M.J.Paine, and N.S.Scrutton (2003).
Determination of the redox potentials and electron transfer properties of the FAD- and FMN-binding domains of the human oxidoreductase NR1.
  Eur J Biochem, 270, 1164-1175.  
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PDB code: 1fue
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PDB codes: 1i0r 1i0s
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PDB codes: 1e1k 1e1l 1e1m 1e1n
10924903 H.Matsuda, S.Kimura, and T.Iyanagi (2000).
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PDB code: 1dd7
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PDB code: 1dt6
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PDB codes: 1df1 1qom
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The crystal structure of NADPH:ferredoxin reductase from Azotobacter vinelandii.
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Molecular cloning and expression in Saccharomyces cerevisiae of tobacco NADPH-cytochrome P450 oxidoreductase cDNA.
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