PDBsum entry 2fdu

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Oxidoreductase PDB id
Protein chain
465 a.a. *
SO4 ×2
HEM-D1G ×4
Waters ×1259
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Microsomal p450 2a6 with the inhibitor n,n-dimethyl(5- (pyridin-3-yl)furan-2-yl)methanamine bound
Structure: Cytochrome p450 2a6. Chain: a, b, c, d. Synonym: cypiia6, coumarin 7-hydroxylase, p450 iia3, cyp2a3, p450i. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cyp2a6. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.85Å     R-factor:   0.186     R-free:   0.223
Authors: J.K.Yano,C.D.Stout,E.F.Johnson
Key ref: J.K.Yano et al. (2006). Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization. J Med Chem, 49, 6987-7001. PubMed id: 17125252 DOI: 10.1021/jm060519r
14-Dec-05     Release date:   28-Nov-06    
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Protein chains
Pfam   ArchSchema ?
P11509  (CP2A6_HUMAN) -  Cytochrome P450 2A6
494 a.a.
465 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: 10.1021/jm060519r J Med Chem 49:6987-7001 (2006)
PubMed id: 17125252  
Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization.
J.K.Yano, T.T.Denton, M.A.Cerny, X.Zhang, E.F.Johnson, J.R.Cashman.
A series of 3-heteroaromatic analogues of nicotine were synthesized to delineate structural and mechanistic requirements for selectively inhibiting human cytochrome P450 (CYP) 2A6. Thiophene, substituted thiophene, furan, substituted furan, acetylene, imidazole, substituted imidazole, thiazole, pyrazole, substituted pyrazole, and aliphatic and isoxazol moieties were used to replace the N-methylpyrrolidine ring of nicotine. A number of potent inhibitors were identified, and several exhibited high selectivity for CYP2A6 relative to CYP2E1, -3A4, -2B6, -2C9, -2C19, and -2D6. The majority of these inhibitors elicited type II difference spectra indicating the formation of a coordinate covalent bond to the heme iron. The majority of inhibitors were reversible inhibitors although several mechanism-based inactivators were identified. Most of the inhibitors were also relatively metabolically stable. X-ray crystal structures of CYP2A6 cocrystallized with three furan analogues bearing methanamino side chains indicated that the amine side chain coordinated to the heme iron. The pyridyl moiety was positioned to accept a hydrogen bond from Asn297, and all three inhibitors exhibited orthogonal aromatic-aromatic interactions with protein side chains. For comparison, the cocrystal structure of 4,4'-dipyridyl disulfide was also obtained and showed that the pyridine moiety could assume a different orientation than that observed for the 3-heteroaromatic pyridines examined. For the 3-heteroromatic pyridines, N-methyl and N,N-dimethyl amino groups increased the apparent Ki and distorted helix I of the protein. Substitution of a phenyl ring for the pyridyl ring also increased the apparent Ki, which is likely to reflect the loss of the hydrogen bonding interaction with Asn297. In contrast, inhibitory potency for other P450s was increased, and the selectivity of the phenyl analogues for CYP2A6 was decreased relative to the pyridyl compounds. The results suggest that inhibitors that compliment the active site features of CYP2A6 can exhibit significant selectivity for CYP2A6 relative to other human liver drug-metabolizing P450s.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20851588 K.A.Salminen, A.Meyer, L.Jerabkova, L.E.Korhonen, M.Rahnasto, R.O.Juvonen, P.Imming, and H.Raunio (2011).
Inhibition of human drug metabolizing cytochrome P450 enzymes by plant isoquinoline alkaloids.
  Phytomedicine, 18, 533-538.  
21372408 M.Miyazawa, Y.Kawauchi, Y.Okuno, and Y.Oda (2011).
The novel assay method for nicotine metabolism to cotinine using high performance liquid chromatography.
  Chem Pharm Bull (Tokyo), 59, 295-297.  
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.
  J Mol Evol, 72, 56-71.  
21336516 S.C.Khojasteh, S.Prabhu, J.R.Kenny, J.S.Halladay, and A.Y.Lu (2011).
Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity.
  Eur J Drug Metab Pharmacokinet, 36, 1.  
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.  
20179500 J.F.Cotten, S.A.Forman, J.K.Laha, G.D.Cuny, S.S.Husain, K.W.Miller, H.H.Nguyen, E.W.Kelly, D.Stewart, A.Liu, and D.E.Raines (2010).
Carboetomidate: a pyrrole analog of etomidate designed not to suppress adrenocortical function.
  Anesthesiology, 112, 637-644.  
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.  
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.  
19683449 S.Ghirmai, M.R.Azar, and J.R.Cashman (2009).
Synthesis and pharmacological evaluation of 6-naltrexamine analogs for alcohol cessation.
  Bioorg Med Chem, 17, 6671-6681.  
19090569 S.Van Damme, and P.Bultinck (2009).
Conceptual DFT properties-based 3D QSAR: analysis of inhibitors of the nicotine metabolizing CYP2A6 enzyme.
  J Comput Chem, 30, 1749-1757.  
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.  
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.  
18022567 G.I.Lepesheva, R.D.Ott, T.Y.Hargrove, Y.Y.Kleshchenko, I.Schuster, W.D.Nes, G.C.Hill, F.Villalta, and M.R.Waterman (2007).
Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth.
  Chem Biol, 14, 1283-1293.  
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.  
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
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.