spacer
spacer

PDBsum entry 1z11

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1z11
Jmol
Contents
Protein chain
467 a.a. *
Ligands
HEM ×4
8MO ×4
Waters ×504
* Residue conservation analysis
PDB id:
1z11
Name: Oxidoreductase
Title: Crystal structure of human microsomal p450 2a6 with methoxsalen bound
Structure: Cytochrome p450, family 2, subfamily a, polypeptide 6. Chain: a, b, c, d. Fragment: catalytic domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cyp2a6. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.05Å     R-factor:   0.219     R-free:   0.261
Authors: J.K.Yano,M.H.Hsu,K.J.Griffin,C.D.Stout,E.F.Johnson
Key ref:
J.K.Yano et al. (2005). Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen. Nat Struct Mol Biol, 12, 822-823. PubMed id: 16086027 DOI: 10.1038/nsmb971
Date:
02-Mar-05     Release date:   16-Aug-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P11509  (CP2A6_HUMAN) -  Cytochrome P450 2A6
Seq:
Struc:
494 a.a.
467 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   6 terms 
  Biological process     small molecule metabolic process   8 terms 
  Biochemical function     oxidoreductase activity     9 terms  

 

 
DOI no: 10.1038/nsmb971 Nat Struct Mol Biol 12:822-823 (2005)
PubMed id: 16086027  
 
 
Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen.
J.K.Yano, M.H.Hsu, K.J.Griffin, C.D.Stout, E.F.Johnson.
 
  ABSTRACT  
 
Human microsomal cytochrome P450 2A6 (CYP2A6) contributes extensively to nicotine detoxication but also activates tobacco-specific procarcinogens to mutagenic products. The CYP2A6 structure shows a compact, hydrophobic active site with one hydrogen bond donor, Asn297, that orients coumarin for regioselective oxidation. The inhibitor methoxsalen effectively fills the active site cavity without substantially perturbing the structure. The structure should aid the design of inhibitors to reduce smoking and tobacco-related cancers.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Comparison of coumarin and methoxsalen binding to CYP2A6. (a) Two views showing the superimposed structures of the coumarin and methoxsalen complexes of CYP2A6. Side chains within 5 of the ligands are rendered as stick figures. Red, oxygen atoms; blue, nitrogen atoms; green, coumarin-complex carbon atoms; yellow, methoxsalen-complex carbon atoms; salmon stick figure, heme group; gray mesh, the solvent-accessible surface of the active site cavity, calculated using VOIDOO12. (b,c) Composite omit [A]-weighted 2|F[o]| -|F[c]| electron density maps contoured at 1 and rendered as blue mesh within 1 of the heme and coumarin (b) or methoxsalen (c). Distances are the mean and standard deviation for the four molecules in the asymmetric unit. Coloring is the same as in a. Molecular graphics were generated using PyMOL (http://pymol.sourceforge.net).
 
  The above figure is reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2005, 12, 822-823) copyright 2005.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21058395 W.Li, J.Shen, G.Liu, Y.Tang, and T.Hoshino (2011).
Exploring coumarin egress channels in human cytochrome P450 2A6 by random acceleration and steered molecular dynamics simulations.
  Proteins, 79, 271-281.  
20061389 G.Chowdhury, M.W.Calcutt, and F.P.Guengerich (2010).
Oxidation of N-Nitrosoalkylamines by human cytochrome P450 2A6: sequential oxidation to aldehydes and carboxylic acids and analysis of reaction steps.
  J Biol Chem, 285, 8031-8044.  
19878193 H.Sun, and D.O.Scott (2010).
Structure-based drug metabolism predictions for drug design.
  Chem Biol Drug Des, 75, 3.  
20078084 J.Sridhar, P.Jin, J.Liu, M.Foroozesh, and C.L.Stevens (2010).
In silico studies of polyaromatic hydrocarbon inhibitors of cytochrome P450 enzymes 1A1, 1A2, 2A6, and 2B1.
  Chem Res Toxicol, 23, 600-607.  
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.
  J Comput Aided Mol Des, 24, 237-256.  
20446763 T.C.Pochapsky, S.Kazanis, and M.Dang (2010).
Conformational plasticity and structure/function relationships in cytochromes P450.
  Antioxid Redox Signal, 13, 1273-1296.  
19434638 A.Chougnet, W.D.Woggon, E.Locher, and B.Schilling (2009).
Synthesis and in vitro activity of heterocyclic inhibitors of CYP2A6 and CYP2A13, two cytochrome P450 enzymes present in the respiratory tract.
  Chembiochem, 10, 1562-1567.  
19555717 I.G.Denisov, D.J.Frank, and S.G.Sligar (2009).
Cooperative properties of cytochromes P450.
  Pharmacol Ther, 124, 151-167.  
19074523 K.E.Schlicht, J.Z.Berg, and S.E.Murphy (2009).
Effect of CYP2A13 active site mutation N297A on metabolism of coumarin and tobacco-specific nitrosamines.
  Drug Metab Dispos, 37, 665-671.  
19104915 M.K.Leong, Y.M.Chen, H.B.Chen, and P.H.Chen (2009).
Development of a New Predictive Model for Interactions with Human Cytochrome P450 2A6 Using Pharmacophore Ensemble/Support Vector Machine (PhE/SVM) Approach.
  Pharm Res, 26, 987.  
19365400 N.Al Koudsi, J.S.Ahluwalia, S.K.Lin, E.M.Sellers, and R.F.Tyndale (2009).
A novel CYP2A6 allele (CYP2A6*35) resulting in an amino-acid substitution (Asn438Tyr) is associated with lower CYP2A6 activity in vivo.
  Pharmacogenomics J, 9, 274-282.  
19251817 N.M.DeVore, B.D.Smith, J.L.Wang, G.H.Lushington, and E.E.Scott (2009).
Key residues controlling binding of diverse ligands to human cytochrome P450 2A enzymes.
  Drug Metab Dispos, 37, 1319-1327.  
19590965 S.F.Zhou, L.P.Yang, Z.W.Zhou, Y.H.Liu, and E.Chan (2009).
Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2.
  AAPS J, 11, 481-494.  
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.  
18622598 E.M.Isin, and F.P.Guengerich (2008).
Substrate binding to cytochromes P450.
  Anal Bioanal Chem, 392, 1019-1030.  
18615618 G.Niu, Z.Wen, S.G.Rupasinghe, R.S.Zeng, M.R.Berenbaum, and M.A.Schuler (2008).
Aflatoxin B1 detoxification by CYP321A1 in Helicoverpa zea.
  Arch Insect Biochem Physiol, 69, 32-45.  
19075644 G.Sharma, and S.Vijayaraghavan (2008).
Nicotinic receptors containing the alpha7 subunit: a model for rational drug design.
  Curr Med Chem, 15, 2921-2932.  
18360915 J.C.Mwenifumbo, N.Al Koudsi, M.K.Ho, Q.Zhou, E.B.Hoffmann, E.M.Sellers, and R.F.Tyndale (2008).
Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of Black African descent.
  Hum Mutat, 29, 679-688.  
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.  
18717595 J.S.Kartha, K.W.Skordos, H.Sun, C.Hall, L.M.Easterwood, C.A.Reilly, E.F.Johnson, and G.S.Yost (2008).
Single mutations change CYP2F3 from a dehydrogenase of 3-methylindole to an oxygenase.
  Biochemistry, 47, 9756-9770.  
18976212 K.N.Myasoedova (2008).
New findings in studies of cytochromes P450.
  Biochemistry (Mosc), 73, 965-969.  
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
17923852 M.Rahnasto, C.Wittekindt, R.O.Juvonen, M.Turpeinen, A.Petsalo, O.Pelkonen, A.Poso, G.Stahl, H.D.Höltje, and H.Raunio (2008).
Identification of inhibitors of the nicotine metabolising CYP2A6 enzyme--an in silico approach.
  Pharmacogenomics J, 8, 328-338.  
18779312 N.M.DeVore, B.D.Smith, M.J.Urban, and E.E.Scott (2008).
Key residues controlling phenacetin metabolism by human cytochrome P450 2A enzymes.
  Drug Metab Dispos, 36, 2582-2590.
PDB code: 3ebs
18495666 N.Oezguen, S.Kumar, A.Hindupur, W.Braun, B.K.Muralidhara, and J.R.Halpert (2008).
Identification and analysis of conserved sequence motifs in cytochrome P450 family 2. Functional and structural role of a motif 187RFDYKD192 in CYP2B enzymes.
  J Biol Chem, 283, 21808-21816.  
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.  
  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.  
17207766 A.J.Annalora, E.Bobrovnikov-Marjon, R.Serda, A.Pastuszyn, S.E.Graham, C.B.Marcus, and J.L.Omdahl (2007).
Hybrid homology modeling and mutational analysis of cytochrome P450C24A1 (CYP24A1) of the Vitamin D pathway: insights into substrate specificity and membrane bound structure-function.
  Arch Biochem Biophys, 460, 262-273.  
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.  
17428784 B.D.Smith, J.L.Sanders, P.R.Porubsky, G.H.Lushington, C.D.Stout, and E.E.Scott (2007).
Structure of the human lung cytochrome P450 2A13.
  J Biol Chem, 282, 17306-17313.
PDB code: 2p85
17209799 E.C.Siu, and R.F.Tyndale (2007).
Non-nicotinic therapies for smoking cessation.
  Annu Rev Pharmacol Toxicol, 47, 541-564.  
17936929 F.P.Guengerich (2007).
Mechanisms of cytochrome P450 substrate oxidation: MiniReview.
  J Biochem Mol Toxicol, 21, 163-168.  
17156750 J.P.Harrelson, K.R.Henne, D.O.Alonso, and S.D.Nelson (2007).
A comparison of substrate dynamics in human CYP2E1 and CYP2A6.
  Biochem Biophys Res Commun, 352, 843-849.  
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.  
17427946 S.G.Rupasinghe, H.Duan, and M.A.Schuler (2007).
Molecular definitions of fatty acid hydroxylases in Arabidopsis thaliana.
  Proteins, 68, 279-293.  
17311915 S.Sansen, J.K.Yano, R.L.Reynald, G.A.Schoch, K.J.Griffin, C.D.Stout, and E.F.Johnson (2007).
Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2.
  J Biol Chem, 282, 14348-14355.
PDB code: 2hi4
16954191 M.Ekroos, and T.Sjögren (2006).
Structural basis for ligand promiscuity in cytochrome P450 3A4.
  Proc Natl Acad Sci U S A, 103, 13682-13687.
PDB codes: 2j0c 2j0d 2v0m
16793528 M.J.de Groot (2006).
Designing better drugs: predicting cytochrome P450 metabolism.
  Drug Discov Today, 11, 601-606.  
16758265 N.Al Koudsi, J.C.Mwenifumbo, E.M.Sellers, N.L.Benowitz, G.E.Swan, and R.F.Tyndale (2006).
Characterization of the novel CYP2A6*21 allele using in vivo nicotine kinetics.
  Eur J Clin Pharmacol, 62, 481-484.  
16352597 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, and A.M.Bridges (2006).
Crystal structure of human cytochrome P450 2D6.
  J Biol Chem, 281, 7614-7622.
PDB code: 2f9q
16207711 D.Kim, Z.L.Wu, and F.P.Guengerich (2005).
Analysis of coumarin 7-hydroxylation activity of cytochrome P450 2A6 using random mutagenesis.
  J Biol Chem, 280, 40319-40327.  
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.