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PDBsum entry 1p45

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1p45
Jmol
Contents
Protein chains
268 a.a. *
Ligands
NAD ×2
TCL ×3
Waters ×45
* Residue conservation analysis
PDB id:
1p45
Name: Oxidoreductase
Title: Targeting tuberculosis and malaria through inhibition of eno reductase: compound activity and structural data
Structure: Enoyl-[acyl-carrier-protein] reductase [nadh]. Chain: a, b. Synonym: nadh-dependent enoyl-acp reductase. Engineered: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: inha or rv1484 or mt1531 or mtcy277.05. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PDB file)
Resolution:
2.60Å     R-factor:   0.228     R-free:   0.290
Authors: M.R.Kuo,H.R.Morbidoni,D.Alland,S.F.Sneddon,B.B.Gourlie,M.M.S M.Leonard,J.S.Gregory,A.D.Janjigian,C.Yee,J.M.Musser,B.N.Kr H.Iwamoto,R.Perozzo,W.R.Jacobs Jr.,J.C.Sacchettini,D.A.Fido Structural Genomics Consortium (Tbsgc)
Key ref:
M.R.Kuo et al. (2003). Targeting tuberculosis and malaria through inhibition of Enoyl reductase: compound activity and structural data. J Biol Chem, 278, 20851-20859. PubMed id: 12606558 DOI: 10.1074/jbc.M211968200
Date:
21-Apr-03     Release date:   16-Sep-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam  
P9WGR1  (INHA_MYCTU) -  Enoyl-[acyl-carrier-protein] reductase [NADH]
Seq:
Struc:
269 a.a.
268 a.a.
Key:    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!
  Biological process     oxidation-reduction process   5 terms 
  Biochemical function     oxidoreductase activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M211968200 J Biol Chem 278:20851-20859 (2003)
PubMed id: 12606558  
 
 
Targeting tuberculosis and malaria through inhibition of Enoyl reductase: compound activity and structural data.
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, D.A.Fidock.
 
  ABSTRACT  
 
Tuberculosis and malaria together result in an estimated 5 million deaths annually. The spread of multidrug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties. Although genetically unrelated, both organisms use a type II fatty-acid synthase system. Enoyl acyl carrier protein reductase (ENR), a key type II enzyme, has been repeatedly validated as an effective antimicrobial target. Using high throughput inhibitor screens with a combinatorial library, we have identified two novel classes of compounds with activity against the M. tuberculosis and P. falciparum enzyme (referred to as InhA and PfENR, respectively). The crystal structure of InhA complexed with NAD+ and one of the inhibitors was determined to elucidate the mode of binding. Structural analysis of InhA with the broad spectrum antimicrobial triclosan revealed a unique stoichiometry where the enzyme contained either a single triclosan molecule, in a configuration typical of other bacterial ENR:triclosan structures, or harbored two triclosan molecules bound to the active site. Significantly, these compounds do not require activation and are effective against wild-type and drug-resistant strains of M. tuberculosis and P. falciparum. Moreover, they provide broader chemical diversity and elucidate key elements of inhibitor binding to InhA for subsequent chemical optimization.
 
  Selected figure(s)  
 
Figure 4.
FIG. 4. Structure of the InhA·triclosan complex with an F[o] - F[c] map contoured at 3 . Triclosan was omitted from the electron density calculations to prevent bias. Helices are depicted in blue, and the -strands are represented in yellow. The two molecules of triclosan occupied the substrate-binding portion of the active site. The hydroxyl groups of the A rings were oriented in opposite directions, whereas the dichlorophenyl rings (B rings) did not stack.
Figure 7.
FIG. 7. Stereo view overlay of Genz-10850 and triclosan reveals that both inhibitors maintain similar hydrogen-bonding interactions with NAD^+ and the catalytic residue Tyr158.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 20851-20859) copyright 2003.  
  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
21094257 N.J.Singh, D.Shin, H.M.Lee, H.T.Kim, H.J.Chang, J.M.Cho, K.S.Kim, and S.Ro (2011).
Structural basis of triclosan resistance.
  J Struct Biol, 174, 173-179.
PDB codes: 3pjd 3pje 3pjf
19779936 A.Kumar, and M.I.Siddiqi (2010).
Receptor based 3D-QSAR to identify putative binders of Mycobacterium tuberculosis Enoyl acyl carrier protein reductase.
  J Mol Model, 16, 877-893.  
  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.  
21210972 K.S.Machado, A.T.Winck, D.D.Ruiz, and O.N.de Souza (2010).
Mining flexible-receptor docking experiments to select promising protein receptor snapshots.
  BMC Genomics, 11, S6.  
21079673 S.L.Kinnings, L.Xie, K.H.Fung, R.M.Jackson, L.Xie, and P.E.Bourne (2010).
The Mycobacterium tuberculosis drugome and its polypharmacological implications.
  PLoS Comput Biol, 6, e1000976.  
20028393 X.Y.Lu, Y.D.Chen, and Q.D.You (2010).
3D-QSAR studies of arylcarboxamides with inhibitory activity on InhA using pharmacophore-based alignment.
  Chem Biol Drug Des, 75, 195-203.  
  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
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
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.  
19578428 S.L.Kinnings, N.Liu, N.Buchmeier, P.J.Tonge, L.Xie, and P.E.Bourne (2009).
Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis.
  PLoS Comput Biol, 5, e1000423.  
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.  
19012578 G.Subba Rao, R.Vijayakrishnan, and M.Kumar (2008).
Structure-based design of a novel class of potent inhibitors of InhA, the enoyl acyl carrier protein reductase from Mycobacterium tuberculosis: a computer modelling approach.
  Chem Biol Drug Des, 72, 444-449.  
18079742 J.C.Sacchettini, E.J.Rubin, and J.S.Freundlich (2008).
Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis.
  Nat Rev Microbiol, 6, 41-52.  
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
17559403 X.Cai, A.Lorraine Fuller, L.R.McDougald, X.Tan, J.Cai, F.Wang, J.C.Sacchettini, and G.Zhu (2007).
Biochemical characterization of enoyl reductase involved in Type II fatty acid synthesis in the intestinal coccidium Eimeria tenella (Phylum Apicomplexa).
  FEMS Microbiol Lett, 272, 238-244.  
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
16849800 B.Zeng, X.Cai, and G.Zhu (2006).
Functional characterization of a fatty acyl-CoA-binding protein (ACBP) from the apicomplexan Cryptosporidium parvum.
  Microbiology, 152, 2355-2363.  
17080030 S.Nwaka, and A.Hudson (2006).
Innovative lead discovery strategies for tropical diseases.
  Nat Rev Drug Discov, 5, 941-955.  
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
16022576 D.Rathore, T.F.McCutchan, M.Sullivan, and S.Kumar (2005).
Antimalarial drugs: current status and new developments.
  Expert Opin Investig Drugs, 14, 871-883.  
15757480 J.Wiesner, and F.Seeber (2005).
The plastid-derived organelle of protozoan human parasites as a target of established and emerging drugs.
  Expert Opin Ther Targets, 9, 23-44.  
15917508 L.Ballell, R.A.Field, K.Duncan, and R.J.Young (2005).
New small-molecule synthetic antimycobacterials.
  Antimicrob Agents Chemother, 49, 2153-2163.  
15727041 R.J.Wilson (2005).
Parasite plastids: approaching the endgame.
  Biol Rev Camb Philos Soc, 80, 129-153.  
15173840 D.A.Fidock, P.J.Rosenthal, S.L.Croft, R.Brun, and S.Nwaka (2004).
Antimalarial drug discovery: efficacy models for compound screening.
  Nat Rev Drug Discov, 3, 509-520.  
15352319 G.Zhu (2004).
Current progress in the fatty acid metabolism in Cryptosporidium parvum.
  J Eukaryot Microbiol, 51, 381-388.  
15205406 O.Zimhony, C.Vilchèze, and W.R.Jacobs (2004).
Characterization of Mycobacterium smegmatis expressing the Mycobacterium tuberculosis fatty acid synthase I (fas1) gene.
  J Bacteriol, 186, 4051-4055.  
17291977 S.Nwaka, L.Riopel, D.Ubben, and J.C.Craft (2004).
Medicines for Malaria Venture new developments in antimalarials.
  Travel Med Infect Dis, 2, 161-170.  
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.  
14675542 C.V.Smith, and J.C.Sacchettini (2003).
Mycobacterium tuberculosis: a model system for structural genomics.
  Curr Opin Struct Biol, 13, 658-664.  
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.