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PDBsum entry 1dfg

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Oxidoreductase PDB id
1dfg
Jmol PyMol
Contents
Protein chains
257 a.a. *
Ligands
NAD-NDT ×2
* Residue conservation analysis
PDB id:
1dfg
Name: Oxidoreductase
Title: X-ray structure of escherichia coli enoyl reductase with bou benzo-diazaborine
Structure: Enoyl acyl carrier protein reductase. Chain: a, b. Synonym: enr. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Biol. unit: Tetramer (from PDB file)
Resolution:
2.50Å     R-factor:   0.173    
Authors: C.Baldock,J.B.Rafferty,D.W.Rice
Key ref:
C.Baldock et al. (1996). A mechanism of drug action revealed by structural studies of enoyl reductase. Science, 274, 2107-2110. PubMed id: 8953047 DOI: 10.1126/science.274.5295.2107
Date:
16-Jan-97     Release date:   28-Jan-98    
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.
257 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: 10.1126/science.274.5295.2107 Science 274:2107-2110 (1996)
PubMed id: 8953047  
 
 
A mechanism of drug action revealed by structural studies of enoyl reductase.
C.Baldock, J.B.Rafferty, S.E.Sedelnikova, P.J.Baker, A.R.Stuitje, A.R.Slabas, T.R.Hawkes, D.W.Rice.
 
  ABSTRACT  
 
Enoyl reductase (ENR), an enzyme involved in fatty acid biosynthesis, is the target for antibacterial diazaborines and the front-line antituberculosis drug isoniazid. Analysis of the structures of complexes of Escherichia coli ENR with nicotinamide adenine dinucleotide and either thienodiazaborine or benzodiazaborine revealed the formation of a covalent bond between the 2' hydroxyl of the nicotinamide ribose and a boron atom in the drugs to generate a tight, noncovalently bound bisubstrate analog. This analysis has implications for the structure-based design of inhibitors of ENR, and similarities to other oxidoreductases suggest that mimicking this molecular linkage may have generic applications in other areas of medicinal chemistry.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. The E. coli ENR tetramer is made up of four subunits, each consisting of a single domain of approximate dimensions 55 by 45 by 45 com- posed of a parallel b sheet of seven strands (b1 to b7), flanked on one side by helices a1, a2, and a7 and on the other by helices a3 to a5, with a further helix, a6, lying along the top of the b sheet. (A) Schematic diagram of a single subunit of the ENR-NAD 1 -thienodiazaborine complex. The ribbon trace of E. coli ENR is shown in red; NAD 1 (blue) and diazaborine (cyan) are shown in an all-atom represen- tation. The loop that orders on diazaborine binding is highlighted in green. [Produced using MIDAS (25).] (B and C) Initial Fourier maps of the NAD 1 -thienodiazaborine complex at 2.2 resolution (B) and of the NAD 1 -benzodiazaborine complex at 2.5 resolution (C) with the final refined structures superimposed. The density (contoured at 1.2s and 0.9s, respectively) was calculated with coefficients 2uFobsu 2 uFcalcu and phases that were calculated from the refined structure from the molecular replacement solution that had been generated with the model of the E. coli ENR-NAD 1 complex, which contained no information about the inhibitor. [Produced using BOBSCRIPT (26), a modified version of MOLSCRIPT (27).] (D) The superposition (based on the nicotinamide and its associated ribose) of the nucleotide-inhibitor complex of ENR into the active site of the nucleotide-substrate complex of DHFR [PDB entry 7DFR (13)]. The Ca backbone trace for DHFR is shown in green, with bound NADP and folate colored turquoise and by atom, respectively; the superimposed NAD 1 and thienodiazaborine of ENR are shown in red and all atom colors, respectively (red, oxygen; white, carbon; blue, nitrogen; yellow, sulfur; green, boron). The covalent bond between the 29 hydroxyl of the nicotinamide ribose and the boron of the diazaborine in ENR is represented by a dotted yellow line. [Produced using MIDAS (25).] When the NAD 1 -thienodi- azaborine complex is fitted into the active site of DHFR, there are some steric clashes between the sulfonyl group and the propyl tail of the diazaborine with parts of the enzyme surface. Nonetheless, there is sufficient space around the 29OH of the nicotinamide ribose to envisage the formation of a linker between the ribose and a folate analog.
Figure 2.
Fig. 2. Schematic repre- sentation of the interac- tions made by the NAD 1 - thienodiazaborine com- plex with the enzyme sur- face and ordered solvent molecules. For NAD 1 , only the nicotinamide ring and the nicotinamide ri- bose are shown. Hydro- gen bonds are represent- ed by dashed lines, hy- drophobic contacts are shown as semicircular arcs, and Wat 1 and Wat 2 are two ordered solvent molecules. [Produced using LIGPLOT (28).]
 
  The above figures are reprinted by permission from the AAAs: Science (1996, 274, 2107-2110) copyright 1996.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21369577 A.S.Evitt, and R.J.Cox (2011).
Synthesis and evaluation of conformationally restricted inhibitors of aspartate semialdehyde dehydrogenase.
  Mol Biosyst, 7, 1564-1575.  
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.  
  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
19151923 R.P.Massengo-Tiassé, and J.E.Cronan (2009).
Diversity in enoyl-acyl carrier protein reductases.
  Cell Mol Life Sci, 66, 1507-1517.  
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.  
18305197 J.Saito, M.Yamada, T.Watanabe, M.Iida, H.Kitagawa, S.Takahata, T.Ozawa, Y.Takeuchi, and F.Ohsawa (2008).
Crystal structure of enoyl-acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitor.
  Protein Sci, 17, 691-699.
PDB codes: 2z6i 2z6j
18663709 S.K.Tipparaju, D.C.Mulhearn, G.M.Klein, Y.Chen, S.Tapadar, M.H.Bishop, S.Yang, J.Chen, M.Ghassemi, B.D.Santarsiero, J.L.Cook, M.Johlfs, A.D.Mesecar, M.E.Johnson, and A.P.Kozikowski (2008).
Design and synthesis of aryl ether inhibitors of the Bacillus anthracis enoyl-ACP reductase.
  ChemMedChem, 3, 1250-1268.
PDB code: 2qio
17112527 D.J.Ferguson, S.A.Campbell, F.L.Henriquez, L.Phan, E.Mui, T.A.Richards, S.P.Muench, M.Allary, J.Z.Lu, S.T.Prigge, F.Tomley, M.W.Shirley, D.W.Rice, R.McLeod, and C.W.Roberts (2007).
Enzymes of type II fatty acid synthesis and apicoplast differentiation and division in Eimeria tenella.
  Int J Parasitol, 37, 33-51.  
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.  
17327670 S.P.Muench, S.T.Prigge, R.McLeod, J.B.Rafferty, M.J.Kirisits, C.W.Roberts, E.J.Mui, and D.W.Rice (2007).
Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents.
  Acta Crystallogr D Biol Crystallogr, 63, 328-338.
PDB codes: 2o2s 2o2y 2o50
17875997 T.Bogdanovich, C.Clark, K.Kosowska-Shick, B.Dewasse, P.McGhee, and P.C.Appelbaum (2007).
Antistaphylococcal activity of CG400549, a new experimental FabI inhibitor, compared with that of other agents.
  Antimicrob Agents Chemother, 51, 4191-4195.  
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.  
  15043388 R.J.Heath, and C.O.Rock (2004).
Fatty acid biosynthesis as a target for novel antibacterials.
  Curr Opin Investig Drugs, 5, 146-153.  
12832774 S.P.Muench, J.B.Rafferty, R.McLeod, D.W.Rice, and S.T.Prigge (2003).
Expression, purification and crystallization of the Plasmodium falciparum enoyl reductase.
  Acta Crystallogr D Biol Crystallogr, 59, 1246-1248.  
12689621 S.Smith, A.Witkowski, and A.K.Joshi (2003).
Structural and functional organization of the animal fatty acid synthase.
  Prog Lipid Res, 42, 289-317.  
14635134 W.L.Duax, V.Pletnev, A.Addlagatta, J.Bruenn, and C.M.Weeks (2003).
Rational proteomics I. Fingerprint identification and cofactor specificity in the short-chain oxidoreductase (SCOR) enzyme family.
  Proteins, 53, 931-943.  
12234833 D.J.Payne, W.H.Miller, V.Berry, J.Brosky, W.J.Burgess, E.Chen, W.E.DeWolf Jr, A.P.Fosberry, R.Greenwood, M.S.Head, D.A.Heerding, C.A.Janson, D.D.Jaworski, P.M.Keller, P.J.Manley, T.D.Moore, K.A.Newlander, S.Pearson, B.J.Polizzi, X.Qiu, S.F.Rittenhouse, C.Slater-Radosti, K.L.Salyers, M.A.Seefeld, M.G.Smyth, D.T.Takata, I.N.Uzinskas, K.Vaidya, N.G.Wallis, S.B.Winram, C.C.Yuan, and W.F.Huffman (2002).
Discovery of a novel and potent class of FabI-directed antibacterial agents.
  Antimicrob Agents Chemother, 46, 3118-3124.  
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.  
11959561 X.He, and K.A.Reynolds (2002).
Purification, characterization, and identification of novel inhibitors of the beta-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus.
  Antimicrob Agents Chemother, 46, 1310-1318.  
11369293 D.J.Payne, P.V.Warren, D.J.Holmes, Y.Ji, and J.T.Lonsdale (2001).
Bacterial fatty-acid biosynthesis: a genomics-driven target for antibacterial drug discovery.
  Drug Discov Today, 6, 537-544.  
11544358 J.W.Campbell, and J.E.Cronan (2001).
Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery.
  Annu Rev Microbiol, 55, 305-332.  
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.  
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.  
10801480 M.Fisher, J.T.Kroon, W.Martindale, A.R.Stuitje, A.R.Slabas, and J.B.Rafferty (2000).
The X-ray structure of Brassica napus beta-keto acyl carrier protein reductase and its implications for substrate binding and catalysis.
  Structure, 8, 339-347.
PDB code: 1edo
10027962 G.J.de Boer, G.J.Pielage, H.J.Nijkamp, A.R.Slabas, J.B.Rafferty, C.Baldock, D.W.Rice, and A.R.Stuitje (1999).
Molecular genetic analysis of enoyl-acyl carrier protein reductase inhibition by diazaborine.
  Mol Microbiol, 31, 443-450.  
  10049298 L.M.McMurry, P.F.McDermott, and S.B.Levy (1999).
Genetic evidence that InhA of Mycobacterium smegmatis is a target for triclosan.
  Antimicrob Agents Chemother, 43, 711-713.  
  10464225 T.T.Hoang, and H.P.Schweizer (1999).
Characterization of Pseudomonas aeruginosa enoyl-acyl carrier protein reductase (FabI): a target for the antimicrobial triclosan and its role in acylated homoserine lactone synthesis.
  J Bacteriol, 181, 5489-5497.  
  10595560 X.Qiu, C.A.Janson, R.I.Court, M.G.Smyth, D.J.Payne, and S.S.Abdel-Meguid (1999).
Molecular basis for triclosan activity involves a flipping loop in the active site.
  Protein Sci, 8, 2529-2532.
PDB code: 1c14
9652124 B.J.Rawlings (1998).
Biosynthesis of fatty acids and related metabolites.
  Nat Prod Rep, 15, 275-308.  
9871552 M.C.Davis, S.G.Franzblau, and A.R.Martin (1998).
Syntheses and evaluation of benzodiazaborine compounds against M. tuberculosis H37Rv in vitro.
  Bioorg Med Chem Lett, 8, 843-846.  
9375250 C.A.Townsend (1997).
Structural studies of natural product biosynthetic proteins.
  Chem Biol, 4, 721-730.  
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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