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PDBsum entry 1qsg

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1qsg
Jmol PyMol
Contents
Protein chains
(+ 2 more) 258 a.a. *
Ligands
GLC ×8
NAD ×8
TCL ×8
Waters ×1350
* Residue conservation analysis
PDB id:
1qsg
Name: Oxidoreductase
Title: Crystal structure of enoyl reductase inhibition by triclosan
Structure: Enoyl-[acyl-carrier-protein] reductase. Chain: a, b, c, d, e, f, g, h. Synonym: nadh-dependent enoyl-acp reductase. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
1.75Å     R-factor:   0.172     R-free:   0.215
Authors: M.J.Stewart,S.Parikh,G.Xiao,P.J.Tonge,C.Kisker
Key ref:
M.J.Stewart et al. (1999). Structural basis and mechanism of enoyl reductase inhibition by triclosan. J Mol Biol, 290, 859-865. PubMed id: 10398587 DOI: 10.1006/jmbi.1999.2907
Date:
21-Jun-99     Release date:   21-Jul-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P0AEK4  (FABI_ECOLI) -  Enoyl-[acyl-carrier-protein] reductase [NADH] FabI
Seq:
Struc:
262 a.a.
258 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.3.1.9  - Enoyl-[acyl-carrier-protein] reductase (NADH).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An acyl-[acyl-carrier protein] + NAD+ = a trans-2,3-dehydroacyl-[acyl- carrier protein] + NADH
acyl-[acyl-carrier protein]
+
NAD(+)
Bound ligand (Het Group name = NAD)
corresponds exactly
= trans-2,3-dehydroacyl-[acyl- carrier protein]
+ NADH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   2 terms 
  Biological process     oxidation-reduction process   9 terms 
  Biochemical function     oxidoreductase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1006/jmbi.1999.2907 J Mol Biol 290:859-865 (1999)
PubMed id: 10398587  
 
 
Structural basis and mechanism of enoyl reductase inhibition by triclosan.
M.J.Stewart, S.Parikh, G.Xiao, P.J.Tonge, C.Kisker.
 
  ABSTRACT  
 
The enoyl-acyl carrier protein reductase (ENR) is involved in bacterial fatty acid biosynthesis and is the target of the antibacterial diazaborine compounds and the front-line antituberculosis drug isoniazid. Recent studies suggest that ENR is also the target for the broad-spectrum biocide triclosan. The 1.75 A crystal structure of EnvM, the ENR from Escherichia coli, in complex with triclosan and NADH reveals that triclosan binds specifically to EnvM. These data provide a molecular mechanism for the antibacterial activity of triclosan and substantiate the hypothesis that its activity results from inhibition of a specific cellular target rather than non-specific disruption of the bacterial cell membrane. This has important implications for the emergence of drug-resistant bacteria, since triclosan is an additive in many personal care products such as toothpastes, mouthwashes and soaps. Based on this structure, rational design of triclosan derivatives is possible which might be effective against recently identified triclosan-resistant bacterial strains.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Structure of triclosan. (a) Structure of 2,4,4′-trichloro-2′-hydroxydiphenyl ether (triclosan). (b) F[o]−F[c] electron density omit refinement map contoured at 3Σ around the triclosan and NADH. NADH and triclosan were omitted from the model, which was subjected to ten cycles of maximum likelihood refinement in REFMAC.
Figure 3.
Figure 3. The inhibitor binding site. (a) Superposition of the triclosan and diazaborine inhibited EnvM structures. Regions in which the polypeptide chains differ are shown in red (triclosan inhibited form) and blue (diazaborine inhibited form). NADH and triclosan are shown in ball-and-stick representation. (b) Schematic drawing of triclosan-protein and triclosan-NADH interactions. Ball-and-stick representation of triclosan and the nicotinamide moiety of the cofactor. Hydrogen bonds are indicated by gray dotted lines and hydrophobic interactions by thick blue dotted lines. (c) Stereo view of the EnvM-triclosan and EnvM-benzodiazaborine complexes. The inhibitors and the cofactors are shown in all-bonds representation with triclosan in red and benzodiazaborine in blue. Residues involved in the formation of the binding pocket are shown in ball-and-stick representation.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (1999, 290, 859-865) copyright 1999.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21280175 K.Maity, T.Banerjee, N.Prabakaran, N.Surolia, A.Surolia, and K.Suguna (2011).
Effect of substrate binding loop mutations on the structure, kinetics, and inhibition of enoyl acyl carrier protein reductase from plasmodium falciparum.
  IUBMB Life, 63, 30-41.
PDB codes: 3am3 3am4 3am5
21393229 N.Liu, J.E.Cummings, K.England, R.A.Slayden, and P.J.Tonge (2011).
Mechanism and inhibition of the FabI enoyl-ACP reductase from Burkholderia pseudomallei.
  J Antimicrob Chemother, 66, 564-573.  
20158608 A.Gurvitz (2010).
Triclosan inhibition of mycobacterial InhA in Saccharomyces cerevisiae: yeast mitochondria as a novel platform for in vivo antimycolate assays.
  Lett Appl Microbiol, 50, 399-405.  
20055482 H.Lu, and P.J.Tonge (2010).
Mechanism and inhibition of the FabV enoyl-ACP reductase from Burkholderia mallei.
  Biochemistry, 49, 1281-1289.  
20124342 L.Lim, and G.I.McFadden (2010).
The evolution, metabolism and functions of the apicoplast.
  Philos Trans R Soc Lond B Biol Sci, 365, 749-763.  
19652324 A.I.Ramos, S.S.Braga, and F.A.Almeida Paz (2009).
Triclosan.
  Acta Crystallogr C, 65, o404-o405.  
  19206187 H.Lu, K.England, C.am Ende, J.J.Truglio, S.Luckner, B.G.Reddy, N.L.Marlenee, S.E.Knudson, D.L.Knudson, R.A.Bowen, C.Kisker, R.A.Slayden, and P.J.Tonge (2009).
Slow-onset inhibition of the FabI enoyl reductase from francisella tularensis: residence time and in vivo activity.
  ACS Chem Biol, 4, 221-231.
PDB code: 2jjy
19734171 K.England, C.am Ende, H.Lu, T.J.Sullivan, N.L.Marlenee, R.A.Bowen, S.E.Knudson, D.L.Knudson, P.J.Tonge, and R.A.Slayden (2009).
Substituted diphenyl ethers as a broad-spectrum platform for the development of chemotherapeutics for the treatment of tularaemia.
  J Antimicrob Chemother, 64, 1052-1061.  
19604480 S.R.Luckner, C.A.Machutta, P.J.Tonge, and C.Kisker (2009).
Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin.
  Structure, 17, 1004-1013.
PDB codes: 2wgd 2wge 2wgf 2wgg
18457948 C.W.am Ende, S.E.Knudson, N.Liu, J.Childs, T.J.Sullivan, M.Boyne, H.Xu, Y.Gegina, D.L.Knudson, F.Johnson, C.A.Peloquin, R.A.Slayden, and P.J.Tonge (2008).
Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors.
  Bioorg Med Chem Lett, 18, 3029-3033.  
18172620 M.Farré, D.Asperger, L.Kantiani, S.González, M.Petrovic, and D.Barceló (2008).
Assessment of the acute toxicity of triclosan and methyl triclosan in wastewater based on the bioluminescence inhibition of Vibrio fischeri.
  Anal Bioanal Chem, 390, 1999-2007.  
17879346 H.H.Lee, J.Moon, and S.W.Suh (2007).
Crystal structure of the Helicobacter pylori enoyl-acyl carrier protein reductase in complex with hydroxydiphenyl ether compounds, triclosan and diclosan.
  Proteins, 69, 691-694.
PDB codes: 2pd3 2pd4
  17329825 K.H.Kim, J.K.Park, B.H.Ha, J.H.Moon, and E.E.Kim (2007).
Crystallization and preliminary X-ray crystallographic analysis of enoyl-ACP reductase III (FabL) from Bacillus subtilis.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 246-248.  
17359226 T.M.Hamill, B.F.Gilmore, D.S.Jones, and S.P.Gorman (2007).
Strategies for the development of the urinary catheter.
  Expert Rev Med Devices, 4, 215-225.  
17723305 X.He, A.Alian, and P.R.Ortiz de Montellano (2007).
Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.
  Bioorg Med Chem, 15, 6649-6658.
PDB code: 2nsd
16681460 B.H.Chew, M.Duvdevani, and J.D.Denstedt (2006).
New developments in ureteral stent design, materials and coatings.
  Expert Rev Med Devices, 3, 395-403.  
16622641 S.Farrell, R.A.Baker, M.Somogyi-Mann, J.J.Witt, and R.W.Gerlach (2006).
Oral malodor reduction by a combination of chemotherapeutical and mechanical treatments.
  Clin Oral Investig, 10, 157-163.  
17012233 S.Rafi, P.Novichenok, S.Kolappan, X.Zhang, C.F.Stratton, R.Rawat, C.Kisker, C.Simmerling, and P.J.Tonge (2006).
Structure of acyl carrier protein bound to FabI, the FASII enoyl reductase from Escherichia coli.
  J Biol Chem, 281, 39285-39293.
PDB code: 2fhs
17034137 X.He, A.Alian, R.Stroud, and P.R.Ortiz de Montellano (2006).
Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis.
  J Med Chem, 49, 6308-6323.
PDB codes: 4trj 4tzk 4tzt 4u0j 4u0k
16648134 Y.M.Zhang, S.W.White, and C.O.Rock (2006).
Inhibiting bacterial fatty acid synthesis.
  J Biol Chem, 281, 17541-17544.  
  18360573 J.Y.Maillard (2005).
Antimicrobial biocides in the healthcare environment: efficacy, usage, policies, and perceived problems.
  Ther Clin Risk Manag, 1, 307-320.  
15952903 S.W.White, J.Zheng, Y.M.Zhang, and Rock (2005).
The structural biology of type II fatty acid biosynthesis.
  Annu Rev Biochem, 74, 791-831.  
15726819 Y.M.Zhang, Y.J.Lu, and C.O.Rock (2004).
The reductase steps of the type II fatty acid synthase as antimicrobial targets.
  Lipids, 39, 1055-1060.  
12606558 M.R.Kuo, H.R.Morbidoni, D.Alland, S.F.Sneddon, B.B.Gourlie, M.M.Staveski, M.Leonard, J.S.Gregory, A.D.Janjigian, C.Yee, J.M.Musser, B.Kreiswirth, H.Iwamoto, R.Perozzo, W.R.Jacobs, J.C.Sacchettini, and D.A.Fidock (2003).
Targeting tuberculosis and malaria through inhibition of Enoyl reductase: compound activity and structural data.
  J Biol Chem, 278, 20851-20859.
PDB codes: 1p44 1p45
12692093 P.Gilbert, and A.J.McBain (2003).
Potential impact of increased use of biocides in consumer products on prevalence of antibiotic resistance.
  Clin Microbiol Rev, 16, 189-208.  
12192068 C.A.Bottoms, P.E.Smith, and J.J.Tanner (2002).
A structurally conserved water molecule in Rossmann dinucleotide-binding domains.
  Protein Sci, 11, 2125-2137.  
12037321 H.H.Lee, J.Yun, J.Moon, B.W.Han, B.I.Lee, J.Y.Lee, and S.W.Suh (2002).
Crystallization and preliminary X-ray crystallographic analysis of enoyl-acyl carrier protein reductase from Helicobacter pylori.
  Acta Crystallogr D Biol Crystallogr, 58, 1071-1073.  
12000609 J.Y.Maillard (2002).
Bacterial target sites for biocide action.
  J Appl Microbiol, 92, 16S-27S.  
12000613 K.Poole (2002).
Mechanisms of bacterial biocide and antibiotic resistance.
  J Appl Microbiol, 92, 55S-64S.  
11792710 R.Perozzo, M.Kuo, A.S.Sidhu, J.T.Valiyaveettil, R.Bittman, W.R.Jacobs, D.A.Fidock, and J.C.Sacchettini (2002).
Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase.
  J Biol Chem, 277, 13106-13114.
PDB codes: 1nhg 1nhw 1nnu 1vrw
12230552 Y.Kallberg, U.Oppermann, H.Jörnvall, and B.Persson (2002).
Short-chain dehydrogenases/reductases (SDRs).
  Eur J Biochem, 269, 4409-4417.  
11180655 E.B.Martin, L.P.Mansfield, A.Smith, and S.J.Forsythe (2001).
Inhibition of light emission from the bioluminescent bacterium Vibrio fischeri after exposure to triclosan and related hygiene care products.
  Luminescence, 16, 29-32.  
11506900 H.P.Schweizer (2001).
Triclosan: a widely used biocide and its link to antibiotics.
  FEMS Microbiol Lett, 202, 1-7.  
11550073 M.P.Groziak (2001).
Boron therapeutics on the horizon.
  Am J Ther, 8, 321-328.  
11591436 R.J.Heath, S.W.White, and C.O.Rock (2001).
Lipid biosynthesis as a target for antibacterial agents.
  Prog Lipid Res, 40, 467-497.  
10975456 A.W.Munro, P.Taylor, and M.D.Walkinshaw (2000).
Structures of redox enzymes.
  Curr Opin Biotechnol, 11, 369-376.  
10841782 K.L.Fillgrove, and V.E.Anderson (2000).
Orientation of coenzyme A substrates, nicotinamide and active site functional groups in (Di)enoyl-coenzyme A reductases.
  Biochemistry, 39, 7001-7011.  
11069675 R.A.Slayden, R.E.Lee, and C.E.Barry (2000).
Isoniazid affects multiple components of the type II fatty acid synthase system of Mycobacterium tuberculosis.
  Mol Microbiol, 38, 514-525.  
10671494 R.J.Heath, J.Li, G.E.Roland, and C.O.Rock (2000).
Inhibition of the Staphylococcus aureus NADPH-dependent enoyl-acyl carrier protein reductase by triclosan and hexachlorophene.
  J Biol Chem, 275, 4654-4659.  
10869170 S.L.Parikh, G.Xiao, and P.J.Tonge (2000).
Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid.
  Biochemistry, 39, 7645-7650.  
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.

 

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