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PDBsum entry 2h7i

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Oxidoreductase PDB id
2h7i
Jmol
Contents
Protein chain
268 a.a. *
Ligands
NAD
566
Waters ×342
* Residue conservation analysis
Superseded by: 4u0j
PDB id:
2h7i
Name: Oxidoreductase
Title: Crystal structure of mycobacterium tuberculosis enoyl reduct complexed with 1-cyclohexyl-5-oxo-n-phenylpyrrolidine-3-car
Structure: Enoyl-[acyl-carrier-protein] reductase [nadh]. Chain: a. Synonym: nadh- dependent enoyl-acp reductase. Engineered: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 83332. Strain: h37rv. Gene: inha. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
1.62Å     R-factor:   0.198     R-free:   0.216
Authors: X.He,A.Alian,R.Stroud,P.R.Ortiz De Montellano
Key ref: X.He et al. (2006). Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. J Med Chem, 49, 6308-6323. PubMed id: 17034137 DOI: 10.1021/jm060715y
Date:
02-Jun-06     Release date:   31-Oct-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam  
P0A5Y6  (INHA_MYCTU) - 
Key:    Secondary structure

 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     cell wall   2 terms 
  Biological process     oxidation-reduction process   5 terms 
  Biochemical function     oxidoreductase activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm060715y J Med Chem 49:6308-6323 (2006)
PubMed id: 17034137  
 
 
Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis.
X.He, A.Alian, R.Stroud, P.R.Ortiz de Montellano.
 
  ABSTRACT  
 
In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antituberculosis agent with novel structures. InhA, the enoyl acyl carrier protein reductase (ENR) from M. tuberculosis, is one of the key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective antimicrobial target. We report here the discovery, through high-throughput screening, of a series of pyrrolidine carboxamides as a novel class of potent InhA inhibitors. Crystal structures of InhA complexed with three inhibitors have been used to elucidate the inhibitor binding mode. The potency of the lead compound was improved over 160-fold by subsequent optimization through iterative microtiter library synthesis followed by in situ activity screening without purification. Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21397998 Y.Izumizono, S.Arevalo, Y.Koseki, M.Kuroki, and S.Aoki (2011).
Identification of novel potential antibiotics for tuberculosis by in silico structure-based drug screening.
  Eur J Med Chem, 46, 1849-1856.  
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.  
20675481 S.Dong, S.A.McPherson, Y.Wang, M.Li, P.Wang, C.L.Turnbough, and D.G.Pritchard (2010).
Characterization of the enzymes encoded by the anthrose biosynthetic operon of Bacillus anthracis.
  J Bacteriol, 192, 5053-5062.  
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.  
21143326 V.Molle, G.Gulten, C.Vilchèze, R.Veyron-Churlet, I.Zanella-Cléon, J.C.Sacchettini, W.R.Jacobs, and L.Kremer (2010).
Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis.
  Mol Microbiol, 78, 1591-1605.
PDB codes: 3oew 3oey 3of2
20925693 V.Virsdoia, M.S.Shaikh, A.Manvar, B.Desai, A.Parecha, R.Loriya, K.Dholariya, G.Patel, V.Vora, K.Upadhyay, K.Denish, A.Shah, and E.C.Coutinho (2010).
Screening for in vitro antimycobacterial activity and three-dimensional quantitative structure-activity relationship (3D-QSAR) study of 4-(arylamino)coumarin derivatives.
  Chem Biol Drug Des, 76, 412-424.  
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.  
20028396 Y.Kawasaki, E.E.Chufan, V.Lafont, K.Hidaka, Y.Kiso, L.Mario Amzel, and E.Freire (2010).
How much binding affinity can be gained by filling a cavity?
  Chem Biol Drug Des, 75, 143-151.
PDB codes: 3kdb 3kdc 3kdd
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.  
18519725 A.A.Miller, G.L.Bundy, J.E.Mott, J.E.Skepner, T.P.Boyle, D.W.Harris, A.E.Hromockyj, K.R.Marotti, G.E.Zurenko, J.B.Munzner, M.T.Sweeney, G.F.Bammert, J.C.Hamel, C.W.Ford, W.Z.Zhong, D.R.Graber, G.E.Martin, F.Han, L.A.Dolak, E.P.Seest, J.C.Ruble, G.M.Kamilar, J.R.Palmer, L.S.Banitt, A.R.Hurd, and M.R.Barbachyn (2008).
Discovery and characterization of QPT-1, the progenitor of a new class of bacterial topoisomerase inhibitors.
  Antimicrob Agents Chemother, 52, 2806-2812.  
18626672 A.Kumar, and M.I.Siddiqi (2008).
CoMFA based de novo design of pyrrolidine carboxamides as inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis.
  J Mol Model, 14, 923-935.  
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.  
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
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
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.