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PDBsum entry 1d7o

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Oxidoreductase PDB id
1d7o
Jmol
Contents
Protein chain
297 a.a. *
Ligands
NAD
TCL
Waters ×88
* Residue conservation analysis
PDB id:
1d7o
Name: Oxidoreductase
Title: Crystal structure of brassica napus enoyl acyl carrier prote reductase complexed with NAD and triclosan
Structure: Enoyl-[acyl-carrier protein] reductase (nadh) pre chain: a. Engineered: yes
Source: Brassica napus. Rape. Organism_taxid: 3708. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PDB file)
Resolution:
1.90Å     R-factor:   0.162     R-free:   0.225
Authors: A.Roujeinikova,C.Levy,S.Rowsell,S.Sedelnikova,P.J.Baker,C.A. A.Mistry,J.G.Colls,R.Camble,A.R.Stuitje,A.R.Slabas,J.B.Raff R.A.Pauptit,R Viner,D.W.Rice
Key ref:
A.Roujeinikova et al. (1999). Crystallographic analysis of triclosan bound to enoyl reductase. J Mol Biol, 294, 527-535. PubMed id: 10610777 DOI: 10.1006/jmbi.1999.3240
Date:
19-Oct-99     Release date:   08-Nov-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P80030  (FABI_BRANA) -  Enoyl-[acyl-carrier-protein] reductase [NADH], chloroplastic
Seq:
Struc:
385 a.a.
297 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

 

 
    reference    
 
 
DOI no: 10.1006/jmbi.1999.3240 J Mol Biol 294:527-535 (1999)
PubMed id: 10610777  
 
 
Crystallographic analysis of triclosan bound to enoyl reductase.
A.Roujeinikova, C.W.Levy, S.Rowsell, S.Sedelnikova, P.J.Baker, C.A.Minshull, A.Mistry, J.G.Colls, R.Camble, A.R.Stuitje, A.R.Slabas, J.B.Rafferty, R.A.Pauptit, R.Viner, D.W.Rice.
 
  ABSTRACT  
 
Molecular genetic studies with strains of Escherichia coli resistant to triclosan, an ingredient of many anti-bacterial household goods, have suggested that this compound works by acting as an inhibitor of enoyl reductase (ENR) and thereby blocking lipid biosynthesis. We present structural analyses correlated with inhibition data, on the complexes of E. coli and Brassica napus ENR with triclosan and NAD(+) which reveal how triclosan acts as a site-directed, picomolar inhibitor of the enzyme by mimicking its natural substrate. Elements of both the protein and the nucleotide cofactor play important roles in triclosan recognition, providing an explanation for the factors controlling its tight binding to the enzyme and for the emergence of triclosan resistance.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. (a) Stereo view of the triclosan binding sites of the superimposed B. napus ENR-NAD^+-triclosan and E. coli ENR-NAD^+-triclosan complexes (based on the overlap of 204 C^a atoms with an rmsd of 0.8 Å). The carbon atoms are coloured magenta in the B. napus ENR ternary complex and yellow in the E. coli ENR complex, nitrogen atoms are shown in blue, oxygen atoms in red, and chlorine atoms in green. Residues are labelled in E. coli ENR. Only the nicotinamide ring and associated ribose of the nucleotide cofactor are shown (produced using SYBYL v5.41, Tripos Associates Inc, St Louis, USA). (b) Ribbon diagram of the triclosan binding sites of the superimposed B. napus ENR-NAD^+-triclosan and E. coli ENR-NAD^+-triclosan complexes. The cofactor and triclosan molecules are only shown for the E. coli ENR complex with carbon atoms coloured black, oxygen atoms in red, nitrogen atoms in blue, phosphorus atoms in magenta and chlorine atoms in green. The backbone atoms are shown in grey for B. napusENR A138G and orange for E. coli ENR. The equivalent loops 192-202 (E. coli ENR) and 236-246 (B. napusENR A138G) are coloured yellow and purple, respectively, and their difference in position is clear. (c) An illustration of the relative locations of the residues G93, M159 and F203 in the triclosan binding site of E. coli ENR. Substitutions at these positions lead to triclosan resistance (see the text). The triclosan and NAD^+ moieties are coloured as described in (b). (b) and (c) Produced using MIDAS [Ferrin et al 1988].
Figure 3.
Figure 3. (a) Stereo view of the superposition of triclosan and diazaborine molecules bound to E. coli ENR in their respective complexes (based on the overlap of 246 C^a atoms with an rmsd of 0.2 Å). The protein structures are essentially identical and have been omitted for clarity, and only the nicotinamide ring and associated ribose and phosphate moieties of the nucleotide cofactor together with the two inhibitors are shown. The diagram illustrates how similarly triclosan and diazaborine occupy the same binding site. The NAD^+ fragment and triclosan are shown in atom colours with oxygen in red, nitrogen in blue, carbon in grey, phosphorous in magenta and chlorine in green. Thienodiazaborine is represented in blue with the boron atom coloured in yellow. The covalent bond between the boron of the diazaborine and the 2'-OH group of the nicotinamide ribose formed upon diazaborine binding is not shown. (b) Stereo view of the superposition of bound triclosan and a model for the enolate anion substrate intermediate showing how triclosan mimics the substrate by the similarity in binding of part of its phenolic ring and of the proposed structure of the substrate. Triclosan, the NAD^+ nicotinamide ring and associated ribose are coloured as described for (a); the substrate's carbon atoms are cyan. Proposed locations of the phosphopantetheine arm (ACP) and growing acyl chain (R) of the substrate are marked. (a) and (b) Produced using MIDAS [Ferrin et al 1988].
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (1999, 294, 527-535) copyright 1999.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20363786 B.F.Pycke, G.Vanermen, P.Monsieurs, H.De Wever, M.Mergeay, W.Verstraete, and N.Leys (2010).
Toxicogenomic response of Rhodospirillum rubrum S1H to the micropollutant triclosan.
  Appl Environ Microbiol, 76, 3503-3513.  
20055482 H.Lu, and P.J.Tonge (2010).
Mechanism and inhibition of the FabV enoyl-ACP reductase from Burkholderia mallei.
  Biochemistry, 49, 1281-1289.  
20221654 R.A.Ward (2010).
Using protein-ligand docking to assess the chemical tractability of inhibiting a protein target.
  J Mol Model, 16, 1833-1843.  
19662054 A.Blinkhorn, P.M.Bartold, M.P.Cullinan, T.E.Madden, R.I.Marshall, S.L.Raphael, and G.J.Seymour (2009).
Is there a role for triclosan/copolymer toothpaste in the management of periodontal disease?
  Br Dent J, 207, 117-125.  
19652324 A.I.Ramos, S.S.Braga, and F.A.Almeida Paz (2009).
Triclosan.
  Acta Crystallogr C, 65, o404-o405.  
19130456 J.S.Freundlich, F.Wang, C.Vilchèze, G.Gulten, R.Langley, G.A.Schiehser, D.P.Jacobus, W.R.Jacobs, and J.C.Sacchettini (2009).
Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis.
  ChemMedChem, 4, 241-248.
PDB codes: 3fne 3fnf 3fng 3fnh
19151923 R.P.Massengo-Tiassé, and J.E.Cronan (2009).
Diversity in enoyl-acyl carrier protein reductases.
  Cell Mol Life Sci, 66, 1507-1517.  
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: 1jvf 1jw7 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.  
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
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: 2h7i 2h7l 2h7m 2h7n 2h7p 4trj 4tzk 4tzt 4u0j 4u0k
  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.  
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
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.  
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: 1nhd 1nhg 1nhw 1nnu 1vrw
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.  
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.