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PDBsum entry 1lqy

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protein ligands metals links
Hydrolase PDB id
1lqy
Jmol
Contents
Protein chain
184 a.a. *
Ligands
BB2
Metals
_NI ×2
Waters ×261
* Residue conservation analysis
PDB id:
1lqy
Name: Hydrolase
Title: Crystal structure of bacillus stearothermophilus peptide deformylase complexed with antibiotic actinonin
Structure: Peptide deformylase 2. Chain: a. Synonym: pdf 2, polypeptide deformylase 2. Engineered: yes
Source: Geobacillus stearothermophilus. Organism_taxid: 1422. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.90Å     R-factor:   0.161     R-free:   0.242
Authors: M.Mathieu,V.Mikol
Key ref:
J.P.Guilloteau et al. (2002). The crystal structures of four peptide deformylases bound to the antibiotic actinonin reveal two distinct types: a platform for the structure-based design of antibacterial agents. J Mol Biol, 320, 951-962. PubMed id: 12126617 DOI: 10.1016/S0022-2836(02)00549-1
Date:
14-May-02     Release date:   24-Jul-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O31410  (DEF2_GEOSE) -  Peptide deformylase 2
Seq:
Struc:
184 a.a.
184 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   1 term 
  Biochemical function     hydrolase activity     4 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S0022-2836(02)00549-1 J Mol Biol 320:951-962 (2002)
PubMed id: 12126617  
 
 
The crystal structures of four peptide deformylases bound to the antibiotic actinonin reveal two distinct types: a platform for the structure-based design of antibacterial agents.
J.P.Guilloteau, M.Mathieu, C.Giglione, V.Blanc, A.Dupuy, M.Chevrier, P.Gil, A.Famechon, T.Meinnel, V.Mikol.
 
  ABSTRACT  
 
Bacterial peptide deformylase (PDF) belongs to a sub-family of metalloproteases that catalyse the removal of the N-terminal formyl group from newly synthesised proteins. PDF is essential in prokaryotes and conserved throughout the eubacteria. It is therefore considered an attractive target for developing new antibacterial agents. Here, we report the crystal structures of four bacterial deformylases, free or bound to the naturally occurring antibiotic actinonin, including two from the major bacterial pathogens Pseudomonas aeruginosa and Staphylococcus aureus. The overall tertiary structure is essentially conserved but shows significant differences, namely at the C terminus, which are directly related to the deformylase type (i.e. I or II) they belong to. The geometry around the catalytic metal ion exhibits a high level of similarity within the different enzymes, as does the binding mode of actinonin to the various deformylases. However, some significant structural differences are found in the vicinity of the active site, highlighting the structural and molecular requirements for the design of a deformylase inhibitor active against a broad spectrum of bacterial strains.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. (a) Comparison of the active site of PDF. Molecular structure of actinonin and delineation of the sub-sites of the binding pocket. Residues highlighted in green correspond to conserved residues and in yellow to variable residues within the four PDF studied (see also Figure 2). (b) Comparison of the binding sites. The proteins are displayed with a line model where the metal ion is shown as a magenta ball, nitrogen, oxygen and sulfur atoms are represented in blue, red and yellow, respectively. The carbon atoms are shown for E. coli in cyan, B. stearothermophilus in white, S. aureus in orange and P. aeruginosa in dark blue. Variable residues are shown with a ball-and-stick model. Numbering corresponds to that of E. coli PDF.
Figure 5.
Figure 5. Binding mode of actinonin. (a) Binding mode of actinonin to B. stearothermophilus PDF. Protein is displayed using a line model with carbon, nitrogen, oxygen and sulfur atoms shown in white, blue, red and yellow, respectively. The actinonin molecule is represented with its carbon atoms in green. Dotted lines correspond to H-bonds. The numbering of residues corresponds to that of B. stearothermophilus PDF. (b) Overlay of the bound conformation of actinonin to various PDFs with carbon atoms of E. coli in cyan, B. stearothermophilus in white, and P. aeruginosa in dark blue. The superimposition results from the overlay made with the protein atoms.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2002, 320, 951-962) copyright 2002.  
  Figures were selected by the author.  

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.  
20656778 P.Lin, T.Hu, J.Hu, W.Yu, C.Han, J.Zhang, G.Qin, K.Yu, F.Götz, X.Shen, H.Jiang, and D.Qu (2010).
Characterization of peptide deformylase homologues from Staphylococcus epidermidis.
  Microbiology, 156, 3194-3202.  
19217394 A.R.Kinjo, and H.Nakamura (2009).
Comprehensive structural classification of ligand-binding motifs in proteins.
  Structure, 17, 234-246.  
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.  
19647435 C.Giglione, S.Fieulaine, and T.Meinnel (2009).
Cotranslational processing mechanisms: towards a dynamic 3D model.
  Trends Biochem Sci, 34, 417-426.  
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
19053131 S.Petit, Y.Duroc, V.Larue, C.Giglione, C.Léon, C.Soulama, A.Denis, F.Dardel, T.Meinnel, and I.Artaud (2009).
Structure-activity relationship analysis of the peptide deformylase inhibitor 5-bromo-1H-indole-3-acetohydroxamic acid.
  ChemMedChem, 4, 261-275.  
18288106 R.Bingel-Erlenmeyer, R.Kohler, G.Kramer, A.Sandikci, S.Antolić, T.Maier, C.Schaffitzel, B.Wiedmann, B.Bukau, and N.Ban (2008).
A peptide deformylase-ribosome complex reveals mechanism of nascent chain processing.
  Nature, 452, 108-111.
PDB codes: 2vhm 2vhn 2vho 2vhp
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.  
  18472972 D.R.Guay (2007).
Drug forecast - the peptide deformylase inhibitors as antibacterial agents.
  Ther Clin Risk Manag, 3, 513-525.  
17163561 F.E.Jacobsen, J.A.Lewis, and S.M.Cohen (2007).
The Design of Inhibitors for Medicinally Relevant Metalloproteins.
  ChemMedChem, 2, 152-171.  
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.  
16882991 J.Cai, C.Han, T.Hu, J.Zhang, D.Wu, F.Wang, Y.Liu, J.Ding, K.Chen, J.Yue, X.Shen, and H.Jiang (2006).
Peptide deformylase is a potential target for anti-Helicobacter pylori drugs: reverse docking, enzymatic assay, and X-ray crystallography validation.
  Protein Sci, 15, 2071-2081.
PDB codes: 2ew5 2ew6 2ew7
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.  
16913833 T.Meinnel, A.Serero, and C.Giglione (2006).
Impact of the N-terminal amino acid on targeted protein degradation.
  Biol Chem, 387, 839-851.  
16144495 D.Chen, and Z.Yuan (2005).
Therapeutic potential of peptide deformylase inhibitors.
  Expert Opin Investig Drugs, 14, 1107-1116.  
16049914 J.H.Moon, J.K.Park, and E.E.Kim (2005).
Structure analysis of peptide deformylase from Bacillus cereus.
  Proteins, 61, 217-220.
PDB codes: 1ws0 1ws1
  16508119 J.K.Park, J.H.Moon, J.H.Kim, and E.E.Kim (2005).
Crystallization and preliminary X-ray crystallographic analysis of peptide deformylase (PDF) from Bacillus cereus in ligand-free and actinonin-bound forms.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 150-152.  
16291698 R.Saxena, and P.K.Chakraborti (2005).
Identification of regions involved in enzymatic stability of peptide deformylase of Mycobacterium tuberculosis.
  J Bacteriol, 187, 8216-8220.  
16192279 S.Fieulaine, C.Juillan-Binard, A.Serero, F.Dardel, C.Giglione, T.Meinnel, and J.L.Ferrer (2005).
The crystal structure of mitochondrial (Type 1A) peptide deformylase provides clear guidelines for the design of inhibitors specific for the bacterial forms.
  J Biol Chem, 280, 42315-42324.
PDB codes: 1zxz 1zy0 1zy1
16239225 Z.Zhou, X.Song, and W.Gong (2005).
Novel conformational states of peptide deformylase from pathogenic bacterium Leptospira interrogans: implications for population shift.
  J Biol Chem, 280, 42391-42396.
PDB codes: 1sv2 1szz 1vev 1vey 1vez
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.  
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
  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.  
15213398 M.Kamo, N.Kudo, W.C.Lee, H.Motoshima, and M.Tanokura (2004).
Crystallization and preliminary X-ray crystallographic analysis of peptide deformylase from Thermus thermophilus HB8.
  Acta Crystallogr D Biol Crystallogr, 60, 1299-1300.  
14532271 A.Serero, C.Giglione, A.Sardini, J.Martinez-Sanz, and T.Meinnel (2003).
An unusual peptide deformylase features in the human mitochondrial N-terminal methionine excision pathway.
  J Biol Chem, 278, 52953-52963.  
12538898 K.J.Smith, C.M.Petit, K.Aubart, M.Smyth, E.McManus, J.Jones, A.Fosberry, C.Lewis, M.Lonetto, and S.B.Christensen (2003).
Structural variation and inhibitor binding in polypeptide deformylase from four different bacterial species.
  Protein Sci, 12, 349-360.
PDB codes: 2ai7 2ai8 2ai9 2aia 2aie
12556209 N.Woodford (2003).
Novel agents for the treatment of resistant Gram-positive infections.
  Expert Opin Investig Drugs, 12, 117-137.  
12472381 C.Giglione, and T.Meinnel (2002).
The situation on antimicrobial agents and chemotherapy in 2002: highlights of the 42nd ICAAC.
  Expert Opin Ther Targets, 6, 691-697.  
12377565 M.B.Schmid (2002).
Structural proteomics: the potential of high-throughput structure determination.
  Trends Microbiol, 10, S27-S31.  
12413557 P.Kuhn, K.Wilson, M.G.Patch, and R.C.Stevens (2002).
The genesis of high-throughput structure-based drug discovery using protein crystallography.
  Curr Opin Chem Biol, 6, 704-710.  
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.