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PDBsum entry 1g27

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
1g27
Jmol
Contents
Protein chains
164 a.a. *
Ligands
BB1 ×3
Metals
_NI ×3
Waters ×76
* Residue conservation analysis
PDB id:
1g27
Name: Hydrolase
Title: Crystal structure of e.Coli polypeptide deformylase complexed with the inhibitor bb-3497
Structure: Polypeptide deformylase. Chain: a, b, c. Synonym: n-formylmethionylaminoacyl-tRNA deformylase, pdf, fms. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562. Gene: def. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.10Å     R-factor:   0.210     R-free:   0.270
Authors: J.M.Clements,P.Beckett,A.Brown,C.Catlin,M.Lobell,S.Palan, W.Thomas,M.Whittaker,P.J.Baker,H.F.Rodgers,V.Barynin, D.W.Rice,M.G.Hunter
Key ref: J.M.Clements et al. (2001). Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor. Antimicrob Agents Chemother, 45, 563-570. PubMed id: 11158755
Date:
17-Oct-00     Release date:   17-Oct-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P0A6K3  (DEF_ECOLI) -  Peptide deformylase
Seq:
Struc:
169 a.a.
164 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.5.1.88  - Peptide deformylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Formyl-L-methionyl peptide + H2O = formate + methionyl peptide
Formyl-L-methionyl peptide
+ H(2)O
= formate
+ methionyl peptide
      Cofactor: Fe(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     translation   3 terms 
  Biochemical function     protein binding     8 terms  

 

 
    reference    
 
 
Antimicrob Agents Chemother 45:563-570 (2001)
PubMed id: 11158755  
 
 
Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor.
J.M.Clements, R.P.Beckett, A.Brown, G.Catlin, M.Lobell, S.Palan, W.Thomas, M.Whittaker, S.Wood, S.Salama, P.J.Baker, H.F.Rodgers, V.Barynin, D.W.Rice, M.G.Hunter.
 
  ABSTRACT  
 
Peptide deformylase (PDF) is an essential bacterial metalloenzyme which deformylates the N-formylmethionine of newly synthesized polypeptides and as such represents a novel target for antibacterial chemotherapy. To identify novel PDF inhibitors, we screened a metalloenzyme inhibitor library and identified an N-formyl-hydroxylamine derivative, BB-3497, and a related natural hydroxamic acid antibiotic, actinonin, as potent and selective inhibitors of PDF. To elucidate the interactions that contribute to the binding affinity of these inhibitors, we determined the crystal structures of BB-3497 and actinonin bound to Escherichia coli PDF at resolutions of 2.1 and 1.75 A, respectively. In both complexes, the active-site metal atom was pentacoordinated by the side chains of Cys 90, His 132, and His 136 and the two oxygen atoms of N-formyl-hydroxylamine or hydroxamate. BB-3497 had activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, and activity against some gram-negative bacteria. Time-kill analysis showed that the mode of action of BB-3497 was primarily bacteriostatic. The mechanism of resistance was via mutations within the formyltransferase gene, as previously described for actinonin. While actinonin and its derivatives have not been used clinically because of their poor pharmacokinetic properties, BB-3497 was shown to be orally bioavailable. A single oral dose of BB-3497 given 1 h after intraperitoneal injection of S. aureus Smith or methicillin-resistant S. aureus protected mice from infection with median effective doses of 8 and 14 mg/kg of body weight, respectively. These data validate PDF as a novel target for the design of a new generation of antibacterial agents.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19922819 A.K.Berg, Q.Yu, S.Y.Qian, M.K.Haldar, and D.K.Srivastava (2010).
Solvent-assisted slow conversion of a dithiazole derivative produces a competitive inhibitor of peptide deformylase.
  Biochim Biophys Acta, 1804, 704-713.  
20607487 D.Zhang, J.Jia, L.Meng, W.Xu, L.Tang, and J.Wang (2010).
Synthesis and preliminary antibacterial evaluation of 2-butyl succinate-based hydroxamate derivatives containing isoxazole rings.
  Arch Pharm Res, 33, 831-842.  
19191548 A.K.Berg, and D.K.Srivastava (2009).
Delineation of alternative conformational states in Escherichia coli peptide deformylase via thermodynamic studies for the binding of actinonin.
  Biochemistry, 48, 1584-1594.  
19627112 C.D.Amero, D.W.Byerly, C.A.McElroy, A.Simmons, and M.P.Foster (2009).
Ligand-induced changes in the structure and dynamics of Escherichia coli peptide deformylase.
  Biochemistry, 48, 7595-7607.  
19236878 S.Escobar-Alvarez, Y.Goldgur, G.Yang, O.Ouerfelli, Y.Li, and D.A.Scheinberg (2009).
Structure and activity of human mitochondrial peptide deformylase, a novel cancer target.
  J Mol Biol, 387, 1211-1228.
PDB codes: 3g5k 3g5p
19171795 Y.Duroc, C.Giglione, and T.Meinnel (2009).
Mutations in three distinct loci cause resistance to peptide deformylase inhibitors in Bacillus subtilis.
  Antimicrob Agents Chemother, 53, 1673-1678.  
18444894 L.G.Dover, A.Bhatt, V.Bhowruth, B.E.Willcox, and G.S.Besra (2008).
New drugs and vaccines for drug-resistant Mycobacterium tuberculosis infections.
  Expert Rev Vaccines, 7, 481-497.  
17429823 B.M.McArdle, and R.J.Quinn (2007).
Identification of protein fold topology shared between different folds inhibited by natural products.
  Chembiochem, 8, 788-798.  
17435169 C.Antczak, D.Shum, S.Escobar, B.Bassit, E.Kim, V.E.Seshan, N.Wu, G.Yang, O.Ouerfelli, Y.M.Li, D.A.Scheinberg, and H.Djaballah (2007).
High-throughput identification of inhibitors of human mitochondrial peptide deformylase.
  J Biomol Screen, 12, 521-535.  
17325780 E.Galardon, M.Giorgi, and I.Artaud (2007).
Modeling the inhibition of peptide deformylase by hydroxamic acids: influence of the sulfur donor.
  Dalton Trans, (), 1047-1052.  
17976009 J.E.Bylander, G.P.Bertenshaw, G.L.Matters, S.J.Hubbard, and J.S.Bond (2007).
Human and mouse homo-oligomeric meprin A metalloendopeptidase: substrate and inhibitor specificities.
  Biol Chem, 388, 1163-1172.  
17333308 J.Y.Lee, M.R.Doddareddy, Y.S.Cho, H.Choo, H.Y.Koh, J.H.Kang, K.T.No, and A.N.Pae (2007).
Comparative QSAR studies on peptide deformylase inhibitors.
  J Mol Model, 13, 543-558.  
17977509 K.T.Nguyen, J.C.Wu, J.A.Boylan, F.C.Gherardini, and D.Pei (2007).
Zinc is the metal cofactor of Borrelia burgdorferi peptide deformylase.
  Arch Biochem Biophys, 468, 217-225.  
16717405 H.Yoneyama, and R.Katsumata (2006).
Antibiotic resistance in bacteria and its future for novel antibiotic development.
  Biosci Biotechnol Biochem, 70, 1060-1075.  
16816197 J.Huang, G.S.Van Aller, A.N.Taylor, J.J.Kerrigan, W.S.Liu, J.M.Trulli, Z.Lai, D.Holmes, K.M.Aubart, J.R.Brown, and M.Zalacain (2006).
Phylogenomic and biochemical characterization of three Legionella pneumophila polypeptide deformylases.
  J Bacteriol, 188, 5249-5257.  
16966397 J.W.Teo, P.Thayalan, D.Beer, A.S.Yap, M.Nanjundappa, X.Ngew, J.Duraiswamy, S.Liung, V.Dartois, M.Schreiber, S.Hasan, M.Cynamon, N.S.Ryder, X.Yang, B.Weidmann, K.Bracken, T.Dick, and K.Mukherjee (2006).
Peptide deformylase inhibitors as potent antimycobacterial agents.
  Antimicrob Agents Chemother, 50, 3665-3673.  
16801408 T.Bogdanovich, K.A.Smith, C.Clark, G.A.Pankuch, G.Lin, P.McGhee, B.Dewasse, and P.C.Appelbaum (2006).
Activity of LBM415 compared to those of 11 other agents against Haemophilus species.
  Antimicrob Agents Chemother, 50, 2323-2329.  
16048914 C.R.Dean, S.Narayan, D.M.Daigle, J.L.Dzink-Fox, X.Puyang, K.R.Bracken, K.E.Dean, B.Weidmann, Z.Yuan, R.Jain, and N.S.Ryder (2005).
Role of the AcrAB-TolC efflux pump in determining susceptibility of Haemophilus influenzae to the novel peptide deformylase inhibitor LBM415.
  Antimicrob Agents Chemother, 49, 3129-3135.  
16144495 D.Chen, and Z.Yuan (2005).
Therapeutic potential of peptide deformylase inhibitors.
  Expert Opin Investig Drugs, 14, 1107-1116.  
15727490 G.Bidaut, K.Suhre, J.M.Claverie, and M.F.Ochs (2005).
Bayesian decomposition analysis of bacterial phylogenomic profiles.
  Am J Pharmacogenomics, 5, 63-70.  
16189089 M.Fonseca-Aten, C.M.Salvatore, A.Mejías, A.M.Ríos, S.Chávez-Bueno, K.Katz, A.M.Gómez, G.H.McCracken, and R.D.Hardy (2005).
Evaluation of LBM415 (NVP PDF-713), a novel peptide deformylase inhibitor, for treatment of experimental Mycoplasma pneumoniae pneumonia.
  Antimicrob Agents Chemother, 49, 4128-4136.  
15793128 T.R.Fritsche, H.S.Sader, R.Cleeland, and R.N.Jones (2005).
Comparative antimicrobial characterization of LBM415 (NVP PDF-713), a new peptide deformylase inhibitor of clinical importance.
  Antimicrob Agents Chemother, 49, 1468-1476.  
14693547 D.Chen, C.Hackbarth, Z.J.Ni, C.Wu, W.Wang, R.Jain, Y.He, K.Bracken, B.Weidmann, D.V.Patel, J.Trias, R.J.White, and Z.Yuan (2004).
Peptide deformylase inhibitors as antibacterial agents: identification of VRC3375, a proline-3-alkylsuccinyl hydroxamate derivative, by using an integrated combinatorial and medicinal chemistry approach.
  Antimicrob Agents Chemother, 48, 250-261.  
14693522 E.Azoulay-Dupuis, J.Mohler, and J.P.Bédos (2004).
Efficacy of BB-83698, a novel peptide deformylase inhibitor, in a mouse model of pneumococcal pneumonia.
  Antimicrob Agents Chemother, 48, 80-85.  
15382235 H.J.Yoon, H.L.Kim, S.K.Lee, H.W.Kim, H.W.Kim, J.Y.Lee, B.Mikami, and S.W.Suh (2004).
Crystal structure of peptide deformylase from Staphylococcus aureus in complex with actinonin, a naturally occurring antibacterial agent.
  Proteins, 57, 639-642.
PDB codes: 1ix1 1q1y
15010544 M.A.Robien, K.T.Nguyen, A.Kumar, I.Hirsh, S.Turley, D.Pei, and W.G.Hol (2004).
An improved crystal form of Plasmodium falciparum peptide deformylase.
  Protein Sci, 13, 1155-1163.
PDB codes: 1rl4 1rqc
15489958 M.D.Lee, Y.She, M.J.Soskis, C.P.Borella, J.R.Gardner, P.A.Hayes, B.M.Dy, M.L.Heaney, M.R.Philips, W.G.Bornmann, F.M.Sirotnak, and D.A.Scheinberg (2004).
Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics.
  J Clin Invest, 114, 1107-1116.  
15353568 R.Gil, F.J.Silva, J.Peretó, and A.Moya (2004).
Determination of the core of a minimal bacterial gene set.
  Microbiol Mol Biol Rev, 68, 518-537.  
15561864 S.Ramanathan-Girish, J.McColm, J.M.Clements, P.Taupin, S.Barrowcliffe, J.Hevizi, S.Safrin, C.Moore, G.Patou, H.Moser, A.Gadd, U.Hoch, V.Jiang, D.Lofland, and K.W.Johnson (2004).
Pharmacokinetics in animals and humans of a first-in-class peptide deformylase inhibitor.
  Antimicrob Agents Chemother, 48, 4835-4842.  
15355422 T.R.Fritsche, G.J.Moet, and R.N.Jones (2004).
Commercial broth microdilution panel validation and reproducibility trials for NVP PDF-713 (LBM 415), a novel inhibitor of bacterial peptide deformylase.
  Clin Microbiol Infect, 10, 857-860.  
12776213 D.Hughes (2003).
Exploiting genomics, genetics and chemistry to combat antibiotic resistance.
  Nat Rev Genet, 4, 432-441.  
12878517 H.Fu, C.Dahlgren, and J.Bylund (2003).
Subinhibitory concentrations of the deformylase inhibitor actinonin increase bacterial release of neutrophil-activating peptides: a new approach to antimicrobial chemotherapy.
  Antimicrob Agents Chemother, 47, 2545-2550.  
12776214 L.Miesel, J.Greene, and T.A.Black (2003).
Genetic strategies for antibacterial drug discovery.
  Nat Rev Genet, 4, 442-456.  
12005434 A.Kumar, K.T.Nguyen, S.Srivathsan, B.Ornstein, S.Turley, I.Hirsh, D.Pei, and W.G.Hol (2002).
Crystals of peptide deformylase from Plasmodium falciparum reveal critical characteristics of the active site for drug design.
  Structure, 10, 357-367.
PDB code: 1jym
12183225 C.J.Hackbarth, D.Z.Chen, J.G.Lewis, K.Clark, J.B.Mangold, J.A.Cramer, P.S.Margolis, W.Wang, J.Koehn, C.Wu, S.Lopez, G.Withers, H.Gu, E.Dunn, R.Kulathila, S.H.Pan, W.L.Porter, J.Jacobs, J.Trias, D.V.Patel, B.Weidmann, R.J.White, and Z.Yuan (2002).
N-alkyl urea hydroxamic acids as a new class of peptide deformylase inhibitors with antibacterial activity.
  Antimicrob Agents Chemother, 46, 2752-2764.  
12070337 D.W.Byerly, C.A.McElroy, and M.P.Foster (2002).
Mapping the surface of Escherichia coli peptide deformylase by NMR with organic solvents.
  Protein Sci, 11, 1850-1853.  
11922862 F.Blasi, P.Braga, M.Cazzola, R.Cosentini, and P.Tarsia (2002).
Therapies in development for community-acquired pneumonia.
  Expert Opin Investig Drugs, 11, 545-552.  
12351843 H.W.Kim, B.W.Han, H.J.Yoon, J.K.Yang, B.I.Lee, H.H.Lee, H.J.Ahn, and S.W.Suh (2002).
Crystallization and preliminary X-ray crystallographic analysis of peptide deformylase from Pseudomonas aeruginosa.
  Acta Crystallogr D Biol Crystallogr, 58, 1874-1875.  
11790623 J.C.Wijkmans, and R.P.Beckett (2002).
Combinatorial chemistry in anti-infectives research.
  Drug Discov Today, 7, 126-132.  
12019092 J.M.Clements, F.Coignard, I.Johnson, S.Chandler, S.Palan, A.Waller, J.Wijkmans, and M.G.Hunter (2002).
Antibacterial activities and characterization of novel inhibitors of LpxC.
  Antimicrob Agents Chemother, 46, 1793-1799.  
12454484 M.S.Harris, J.H.Bock, G.Choi, J.S.Cialdella, K.A.Curry, M.R.Deibel, E.J.Jacobsen, V.P.Marshall, R.W.Murray, A.F.Vosters, C.L.Wolfe, A.W.Yem, and E.T.Baldwin (2002).
Co-crystallization of Staphylococcus aureus peptide deformylase (PDF) with potent inhibitors.
  Acta Crystallogr D Biol Crystallogr, 58, 2153-2156.  
11897602 R.Wise, J.M.Andrews, and J.Ashby (2002).
In vitro activities of peptide deformylase inhibitors against gram-positive pathogens.
  Antimicrob Agents Chemother, 46, 1117-1118.  
11976499 Y.Li, S.Ren, and W.Gong (2002).
Cloning, high-level expression, purification and crystallization of peptide deformylase from Leptospira interrogans.
  Acta Crystallogr D Biol Crystallogr, 58, 846-848.  
12540274 C.Giglione, and T.Meinnel (2001).
Resistance to anti-peptide deformylase drugs.
  Expert Opin Ther Targets, 5, 415-418.  
15992167 C.Giglione, and T.Meinnel (2001).
Peptide deformylase as an emerging target for antiparasitic agents.
  Expert Opin Ther Targets, 5, 41-57.  
11728875 D.McDevitt, and M.Rosenberg (2001).
Exploiting genomics to discover new antibiotics.
  Trends Microbiol, 9, 611-617.  
11502510 P.Margolis, C.Hackbarth, S.Lopez, M.Maniar, W.Wang, Z.Yuan, R.White, and J.Trias (2001).
Resistance of Streptococcus pneumoniae to deformylase inhibitors is due to mutations in defB.
  Antimicrob Agents Chemother, 45, 2432-2435.  
11546610 Z.Yuan, J.Trias, and R.J.White (2001).
Deformylase as a novel antibacterial target.
  Drug Discov Today, 6, 954-961.  
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.