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PDBsum entry 2foi

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
2foi
Jmol
Contents
Protein chains
229 a.a. *
60 a.a. *
Ligands
NAD ×2
JPA ×2
Waters ×55
* Residue conservation analysis
PDB id:
2foi
Name: Oxidoreductase
Title: Synthesis, biological activity, and x-ray crystal structural of diaryl ether inhibitors of malarial enoyl acp reductase.
Structure: Enoyl-acyl carrier reductase. Chain: a, b. Fragment: n-terminal fragment, residues 97-216. Engineered: yes. Enoyl-acyl carrier reductase. Chain: c, d. Fragment: c-terminal fragment, residues 97-156. Engineered: yes
Source: Plasmodium falciparum. Organism_taxid: 36329. Strain: 3d7. Gene: pfenr. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.50Å     R-factor:   0.197     R-free:   0.255
Authors: J.S.Freundlich,H.Shieh,J.W.Anderson,M.Kuo,M.Yu,J.Valderramos L.Karagyozov,H.Tsai,E.Lucumi,W.R.Jacobs Jr.,G.A.Schiehser, D.P.Jacobus,D.A.Fidock,J.C.Sacchettini
Key ref:
J.S.Freundlich et al. (2007). X-ray Structural Analysis of Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase as a Pathway toward the Optimization of Triclosan Antimalarial Efficacy. J Biol Chem, 282, 25436-25444. PubMed id: 17567585 DOI: 10.1074/jbc.M701813200
Date:
13-Jan-06     Release date:   16-Jan-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
C6KSZ2  (C6KSZ2_PLAF7) -  Enoyl-acyl carrier reductase
Seq:
Struc:
432 a.a.
229 a.a.
Protein chains
Pfam   ArchSchema ?
C6KSZ2  (C6KSZ2_PLAF7) -  Enoyl-acyl carrier reductase
Seq:
Struc:
432 a.a.
60 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D: 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: 10.1074/jbc.M701813200 J Biol Chem 282:25436-25444 (2007)
PubMed id: 17567585  
 
 
X-ray Structural Analysis of Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase as a Pathway toward the Optimization of Triclosan Antimalarial Efficacy.
J.S.Freundlich, F.Wang, H.C.Tsai, M.Kuo, H.M.Shieh, J.W.Anderson, L.J.Nkrumah, J.C.Valderramos, M.Yu, T.R.Kumar, S.G.Valderramos, W.R.Jacobs, G.A.Schiehser, D.P.Jacobus, D.A.Fidock, J.C.Sacchettini.
 
  ABSTRACT  
 
The x-ray crystal structures of five triclosan analogs, in addition to that of the isoniazid-NAD adduct, are described in relation to their integral role in the design of potent inhibitors of the malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of the novel 5-substituted analogs exhibit low micromolar potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite and inhibit purified PfENR enzyme with IC(50) values of <200 nm. This study has significantly expanded the knowledge base with regard to the structure-activity relationship of triclosan while affording gains against cultured parasites and purified PfENR enzyme. In contrast to a recent report in the literature, these results demonstrate the ability to improve the in vitro potency of triclosan significantly by replacing the suboptimal 5-chloro group with larger hydrophobic moieties. The biological and x-ray crystallographic data thus demonstrate the flexibility of the active site and point to future rounds of optimization to improve compound potency against purified enzyme and intracellular Plasmodium parasites.
 
  Selected figure(s)  
 
Figure 1.
FIGURE 1. Chemical structures of triclosan and isoniazid.
Figure 2.
FIGURE 2. X-ray crystal structures of ligands bound to PfENR. A, INH-NAD (stick drawing) bound to PfENR (ribbon and tube). The INH isonicotinamide pyridyl nitrogen and the Tyr-267 side chain phenol are hydrogen-bonded to a water molecule (WAT30). The side chain phenol of Tyr-277, the carbonyl of the INH isonicotinamide moiety, and NADH ribose hydroxyl are all hydrogen-bonding to a water molecule (WAT64). Distances shown are in angstroms. B, 15 (stick drawing; gold coloring) bound to PfENR (ribbon and tube) in the presence of NAD^+ (space fill), with an overlay of INH-NAD (stick drawing) bound to PfENR. The enzyme active site accommodates the 5-substituent most evidently by rotation of Phe-368 and movement of Tyr-267. C, 23 (stick drawing) bound to PfENR (ribbon and tube) and NAD^+ (stick drawing), with an overlay of 15 (stick drawing; turquoise blue coloring) bound to PfENR. Phe-368 is colored according to the ligand bound to PfENR NAD^+ atom color (23 bound) or turquoise blue (15 bound). The 2-pyridyl moiety of 23 is engaged in hydrophobic interactions with Pro-314, Phe-368, Ile-369, and Ala-372 and a face-to-face -stacking interaction with Tyr-267. For all PfENR structures in Figs. 2 and 3, key residues are noted in stick format, and parts of the structure are removed for clarity. Both figures were made using the program SwissPDB viewer (63).
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 25436-25444) copyright 2007.  
  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
  20559451 C.Ben Mamoun, S.T.Prigge, and H.Vial (2010).
Targeting the Lipid Metabolic Pathways for the Treatment of Malaria.
  Drug Dev Res, 71, 44-55.  
20131353 G.Kumar, T.Banerjee, N.Kapoor, N.Surolia, and A.Surolia (2010).
SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl-acyl carrier protein reductase.
  IUBMB Life, 62, 204-213.  
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
19191586 P.J.Lee, J.B.Bhonsle, H.W.Gaona, D.P.Huddler, T.N.Heady, M.Kreishman-Deitrick, A.Bhattacharjee, W.F.McCalmont, L.Gerena, M.Lopez-Sanchez, N.E.Roncal, T.H.Hudson, J.D.Johnson, S.T.Prigge, and N.C.Waters (2009).
Targeting the fatty acid biosynthesis enzyme, beta-ketoacyl-acyl carrier protein synthase III (PfKASIII), in the identification of novel antimalarial agents.
  J Med Chem, 52, 952-963.  
19834482 T.N.Wells, P.L.Alonso, and W.E.Gutteridge (2009).
New medicines to improve control and contribute to the eradication of malaria.
  Nat Rev Drug Discov, 8, 879-891.  
  19064257 M.Yu, T.R.Kumar, L.J.Nkrumah, A.Coppi, S.Retzlaff, C.D.Li, B.J.Kelly, P.A.Moura, V.Lakshmanan, J.S.Freundlich, J.C.Valderramos, C.Vilcheze, M.Siedner, J.H.Tsai, B.Falkard, A.B.Sidhu, L.A.Purcell, P.Gratraud, L.Kremer, A.P.Waters, G.Schiehser, D.P.Jacobus, C.J.Janse, A.Ager, W.R.Jacobs, J.C.Sacchettini, V.Heussler, P.Sinnis, and D.A.Fidock (2008).
The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.
  Cell Host Microbe, 4, 567-578.
PDB code: 3f4b
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
17875391 P.Gayathri, H.Balaram, and M.R.Murthy (2007).
Structural biology of plasmodial proteins.
  Curr Opin Struct Biol, 17, 744-754.  
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.