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PDBsum entry 2f9q

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
2f9q
Jmol
Contents
Protein chains
454 a.a. *
Ligands
HEM ×4
SO4 ×2
Waters ×11
* Residue conservation analysis
PDB id:
2f9q
Name: Oxidoreductase
Title: Crystal structure of human cytochrome p450 2d6
Structure: Cytochrome p450 2d6. Chain: a, b, c, d. Synonym: cypiid6. P450-db1. Debrisoquine 4-hydroxylase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cyp2d6. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PQS)
Resolution:
3.00Å     R-factor:   0.232     R-free:   0.286
Authors: P.Rowland
Key ref:
P.Rowland et al. (2006). Crystal structure of human cytochrome P450 2D6. J Biol Chem, 281, 7614-7622. PubMed id: 16352597 DOI: 10.1074/jbc.M511232200
Date:
06-Dec-05     Release date:   20-Dec-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P10635  (CP2D6_HUMAN) -  Cytochrome P450 2D6
Seq:
Struc:
497 a.a.
454 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.1.14.14.1  - Unspecific monooxygenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RH + reduced flavoprotein + O2 = ROH + oxidized flavoprotein + H2O
RH
+ reduced flavoprotein
+ O(2)
= ROH
+ oxidized flavoprotein
+ H(2)O
      Cofactor: Heme-thiolate
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     small molecule metabolic process   15 terms 
  Biochemical function     drug binding     9 terms  

 

 
    Added reference    
 
 
DOI no: 10.1074/jbc.M511232200 J Biol Chem 281:7614-7622 (2006)
PubMed id: 16352597  
 
 
Crystal structure of human cytochrome P450 2D6.
P.Rowland, F.E.Blaney, M.G.Smyth, J.J.Jones, V.R.Leydon, A.K.Oxbrow, C.J.Lewis, M.G.Tennant, S.Modi, D.S.Eggleston, R.J.Chenery, A.M.Bridges.
 
  ABSTRACT  
 
Cytochrome P450 2D6 is a heme-containing enzyme that is responsible for the metabolism of at least 20% of known drugs. Substrates of 2D6 typically contain a basic nitrogen and a planar aromatic ring. The crystal structure of human 2D6 has been solved and refined to 3.0A resolution. The structure shows the characteristic P450 fold as seen in other members of the family, with the lengths and orientations of the individual secondary structural elements being very similar to those seen in 2C9. There are, however, several important differences, the most notable involving the F helix, the F-G loop, the B'helix, beta sheet 4, and part of beta sheet 1, all of which are situated on the distal face of the protein. The 2D6 structure has a well defined active site cavity above the heme group, containing many important residues that have been implicated in substrate recognition and binding, including Asp-301, Glu-216, Phe-483, and Phe-120. The crystal structure helps to explain how Asp-301, Glu-216, and Phe-483 can act as substrate binding residues and suggests that the role of Phe-120 is to control the orientation of the aromatic ring found in most substrates with respect to the heme. The structure has been compared with published homology models and has been used to explain much of the reported site-directed mutagenesis data and help understand the metabolism of several compounds.
 
  Selected figure(s)  
 
Figure 4.
FIGURE 4. Ribbon diagram of the 2D6 structure.
Figure 6.
FIGURE 6. Active site cavity. A, ribbon diagram of the "right foot"-shaped active site cavity, showing the location of the B', F, G, and I helices (labeled). Also shown are the B'-C loop (lower left), the loop between 4-1 and 4-2 (upper right), and the loop between helix K and 1-4 (lower right). The cavity shape was generated using a 1.4-Å radius probe occupied volume. B, close up of the residues surrounding the cavity, with some of the key residues labeled.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 7614-7622) copyright 2006.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20857167 D.Degregorio, S.J.Sadeghi, G.Di Nardo, G.Gilardi, and S.P.Solinas (2011).
Understanding uncoupling in the multiredox centre P450 3A4-BMR model system.
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Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450.
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21116621 N.Kirischian, A.G.McArthur, C.Jesuthasan, B.Krattenmacher, and J.Y.Wilson (2011).
Phylogenetic and functional analysis of the vertebrate cytochrome p450 2 family.
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21188366 T.Schenekar, K.A.Winkler, J.L.Troyer, and S.Weiss (2011).
Isolation and characterization of the CYP2D6 gene in Felidae with comparison to other mammals.
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20387782 D.Fishelovitch, S.Shaik, H.J.Wolfson, and R.Nussinov (2010).
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21038340 G.Rossato, B.Ernst, M.Smiesko, M.Spreafico, and A.Vedani (2010).
Probing small-molecule binding to cytochrome P450 2D6 and 2C9: An in silico protocol for generating toxicity alerts.
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19769330 P.R.Ortiz de Montellano (2010).
Hydrocarbon hydroxylation by cytochrome P450 enzymes.
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20361239 R.J.Unwalla, J.B.Cross, S.Salaniwal, A.D.Shilling, L.Leung, J.Kao, and C.Humblet (2010).
Using a homology model of cytochrome P450 2D6 to predict substrate site of metabolism.
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20446763 T.C.Pochapsky, S.Kazanis, and M.Dang (2010).
Conformational plasticity and structure/function relationships in cytochromes P450.
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18832475 A.M.Yu, J.Qu, M.A.Felmlee, J.Cao, and X.L.Jiang (2009).
Quantitation of human cytochrome P450 2D6 protein with immunoblot and mass spectrometry analysis.
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19858213 B.Zhao, L.Lei, D.G.Vassylyev, X.Lin, D.E.Cane, S.L.Kelly, H.Yuan, D.C.Lamb, and M.R.Waterman (2009).
Crystal structure of albaflavenone monooxygenase containing a moonlighting terpene synthase active site.
  J Biol Chem, 284, 36711-36719.
PDB codes: 3dbg 3el3
19728720 D.Fishelovitch, S.Shaik, H.J.Wolfson, and R.Nussinov (2009).
Theoretical characterization of substrate access/exit channels in the human cytochrome P450 3A4 enzyme: involvement of phenylalanine residues in the gating mechanism.
  J Phys Chem B, 113, 13018-13025.  
19129847 D.Ghosh, J.Griswold, M.Erman, and W.Pangborn (2009).
Structural basis for androgen specificity and oestrogen synthesis in human aromatase.
  Nature, 457, 219-223.
PDB code: 3eqm
19555717 I.G.Denisov, D.J.Frank, and S.G.Sligar (2009).
Cooperative properties of cytochromes P450.
  Pharmacol Ther, 124, 151-167.  
19937844 J.Dapkunas, A.Sazonovas, and P.Japertas (2009).
Probabilistic prediction of the human CYP3A4 and CYP2D6 metabolism sites.
  Chem Biodivers, 6, 2101-2106.  
20040113 M.Freigassner, H.Pichler, and A.Glieder (2009).
wTuning microbial hosts for membrane protein production.
  Microb Cell Fact, 8, 69.  
19638317 M.J.de Groot, F.Wakenhut, G.Whitlock, and R.Hyland (2009).
Understanding CYP2D6 interactions.
  Drug Discov Today, 14, 964-972.  
19448135 M.Subramanian, M.Low, C.W.Locuson, and T.S.Tracy (2009).
CYP2D6-CYP2C9 protein-protein interactions and isoform-selective effects on substrate binding and catalysis.
  Drug Metab Dispos, 37, 1682-1689.  
19817501 S.F.Zhou (2009).
Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I.
  Clin Pharmacokinet, 48, 689-723.  
18922023 C.M.Mosher, M.A.Hummel, T.S.Tracy, and A.E.Rettie (2008).
Functional analysis of phenylalanine residues in the active site of cytochrome P450 2C9.
  Biochemistry, 47, 11725-11734.  
18721112 D.F.Lewis, and Y.Ito (2008).
Human cytochromes P450 in the metabolism of drugs: new molecular models of enzyme-substrate interactions.
  Expert Opin Drug Metab Toxicol, 4, 1181-1186.  
18484912 E.Stjernschantz, N.P.Vermeulen, and C.Oostenbrink (2008).
Computational prediction of drug binding and rationalisation of selectivity towards cytochromes P450.
  Expert Opin Drug Metab Toxicol, 4, 513-527.  
18606741 G.Tai, L.J.Dickmann, N.Matovic, J.J.DeVoss, E.M.Gillam, and A.E.Rettie (2008).
Re-engineering of CYP2C9 to probe acid-base substrate selectivity.
  Drug Metab Dispos, 36, 1992-1997.  
18026129 J.D.Maréchal, C.A.Kemp, G.C.Roberts, M.J.Paine, C.R.Wolf, and M.J.Sutcliffe (2008).
Insights into drug metabolism by cytochromes P450 from modelling studies of CYP2D6-drug interactions.
  Br J Pharmacol, 153, S82-S89.  
18976212 K.N.Myasoedova (2008).
New findings in studies of cytochromes P450.
  Biochemistry (Mosc), 73, 965-969.  
18622752 K.S.Rabe, V.J.Gandubert, M.Spengler, M.Erkelenz, and C.M.Niemeyer (2008).
Engineering and assaying of cytochrome P450 biocatalysts.
  Anal Bioanal Chem, 392, 1059-1073.  
18787124 L.Li, Z.Chang, Z.Pan, Z.Q.Fu, and X.Wang (2008).
Modes of heme binding and substrate access for cytochrome P450 CYP74A revealed by crystal structures of allene oxide synthase.
  Proc Natl Acad Sci U S A, 105, 13883-13888.
PDB codes: 3dam 3dan 3dbm
18816585 N.Levoin, T.Calmels, O.Poupardin-Olivier, O.Labeeuw, D.Danvy, P.Robert, I.Berrebi-Bertrand, C.R.Ganellin, W.Schunack, H.Stark, and M.Capet (2008).
Refined docking as a valuable tool for lead optimization: application to histamine H3 receptor antagonists.
  Arch Pharm (Weinheim), 341, 610-623.  
18698000 N.T.Snider, M.J.Sikora, C.Sridar, T.J.Feuerstein, J.M.Rae, and P.F.Hollenberg (2008).
The endocannabinoid anandamide is a substrate for the human polymorphic cytochrome P450 2D6.
  J Pharmacol Exp Ther, 327, 538-545.  
18818195 P.R.Porubsky, K.M.Meneely, and E.E.Scott (2008).
Structures of human cytochrome P-450 2E1. Insights into the binding of inhibitors and both small molecular weight and fatty acid substrates.
  J Biol Chem, 283, 33698-33707.
PDB codes: 3e4e 3e6i
17922078 Q.B.Su, F.He, X.D.Wang, S.Guan, Z.Y.Xie, L.Y.Wang, Y.J.Lu, L.Q.Gu, Z.S.Huang, X.Chen, M.Huang, and S.F.Zhou (2008).
Biotransformation and pharmacokinetics of the novel anticancer drug, SYUIQ-5, in the rat.
  Invest New Drugs, 26, 119-137.  
18537573 S.Ekins, M.Iyer, M.D.Krasowski, and E.D.Kharasch (2008).
Molecular characterization of CYP2B6 substrates.
  Curr Drug Metab, 9, 363-373.  
18004755 W.Li, Y.Tang, H.Liu, J.Cheng, W.Zhu, and H.Jiang (2008).
Probing ligand binding modes of human cytochrome P450 2J2 by homology modeling, molecular dynamics simulation, and flexible molecular docking.
  Proteins, 71, 938-949.  
18366166 Y.Ding, W.H.Seufert, Z.Q.Beck, and D.H.Sherman (2008).
Analysis of the cryptophycin P450 epoxidase reveals substrate tolerance and cooperativity.
  J Am Chem Soc, 130, 5492-5498.  
18703643 Y.Tu, R.Deshmukh, M.Sivaneri, and G.D.Szklarz (2008).
Application of molecular modeling for prediction of substrate specificity in cytochrome P450 1A2 mutants.
  Drug Metab Dispos, 36, 2371-2380.  
  18607105 Z.Chang, L.Li, Z.Pan, and X.Wang (2008).
Crystallization and preliminary X-ray analysis of allene oxide synthase, cytochrome P450 CYP74A2, from Parthenium argentatum.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 668-670.  
17318599 A.Bonifacio, A.R.Groenhof, P.H.Keizers, C.de Graaf, J.N.Commandeur, N.P.Vermeulen, A.W.Ehlers, K.Lammertsma, C.Gooijer, and G.van der Zwan (2007).
Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study.
  J Biol Inorg Chem, 12, 645-654.  
17534532 A.W.Munro, H.M.Girvan, and K.J.McLean (2007).
Variations on a (t)heme--novel mechanisms, redox partners and catalytic functions in the cytochrome P450 superfamily.
  Nat Prod Rep, 24, 585-609.  
17333164 C.de Graaf, C.Oostenbrink, P.H.Keizers, B.M.van Vugt-Lussenburg, J.N.Commandeur, and N.P.Vermeulen (2007).
Free energies of binding of R- and S-propranolol to wild-type and F483A mutant cytochrome P450 2D6 from molecular dynamics simulations.
  Eur Biophys J, 36, 589-599.  
17559204 D.R.McMasters, R.A.Torres, S.J.Crathern, D.L.Dooney, R.B.Nachbar, R.P.Sheridan, and K.R.Korzekwa (2007).
Inhibition of recombinant cytochrome P450 isoforms 2D6 and 2C9 by diverse drug-like molecules.
  J Med Chem, 50, 3205-3213.  
17500592 J.H.Thomas (2007).
Rapid birth-death evolution specific to xenobiotic cytochrome P450 genes in vertebrates.
  PLoS Genet, 3, e67.  
17983558 J.Moretto, G.Bessard, and F.Stanke-Labesque (2007).
[Immunosuppressive drugs and highly active antiretroviral therapy: pharmacokinetic interactions].
  Therapie, 62, 327-335.  
17487889 K.Saito, H.Dan, K.Masuda, T.Katsu, N.Hanioka, S.Yamamoto, K.Miyano, S.Yamano, and S.Narimatsu (2007).
Stereoselective hexobarbital 3'-hydroxylation by CYP2C19 expressed in yeast cells and the roles of amino acid residues at positions 300 and 476.
  Chirality, 19, 550-558.  
18034311 M.P.Gleeson, A.M.Davis, K.K.Chohan, S.W.Paine, S.Boyer, C.L.Gavaghan, C.H.Arnby, C.Kankkonen, and N.Albertson (2007).
Generation of in-silico cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 inhibition QSAR models.
  J Comput Aided Mol Des, 21, 559-573.  
17705402 P.Lafite, F.André, D.C.Zeldin, P.M.Dansette, and D.Mansuy (2007).
Unusual regioselectivity and active site topology of human cytochrome P450 2J2.
  Biochemistry, 46, 10237-10247.  
17470359 P.Lafite, S.Dijols, D.C.Zeldin, P.M.Dansette, and D.Mansuy (2007).
Selective, competitive and mechanism-based inhibitors of human cytochrome P450 2J2.
  Arch Biochem Biophys, 464, 155-168.  
17549046 S.Ekins, J.Mestres, and B.Testa (2007).
In silico pharmacology for drug discovery: applications to targets and beyond.
  Br J Pharmacol, 152, 21-37.  
17540336 S.Sansen, M.H.Hsu, C.D.Stout, and E.F.Johnson (2007).
Structural insight into the altered substrate specificity of human cytochrome P450 2A6 mutants.
  Arch Biochem Biophys, 464, 197-206.
PDB codes: 2pg5 2pg6 2pg7
17308979 X.B.Pan, L.Wei, H.S.Chen, F.Liu, and Y.Gao (2007).
Liver-derived cell lines QSG-7701 and HepG2 support different HBV replication patterns.
  Arch Virol, 152, 1159-1173.  
17047872 J.Zurek, N.Foloppe, J.N.Harvey, and A.J.Mulholland (2006).
Mechanisms of reaction in cytochrome P450: Hydroxylation of camphor in P450cam.
  Org Biomol Chem, 4, 3931-3937.  
16793528 M.J.de Groot (2006).
Designing better drugs: predicting cytochrome P450 metabolism.
  Drug Discov Today, 11, 601-606.  
16863447 T.Herz, K.Wolf, J.Kraus, and B.Kramer (2006).
4SCan/vADME: intelligent library screening as a shortcut from hits to lead compounds.
  Expert Opin Drug Metab Toxicol, 2, 471-484.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.