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PDBsum entry 1nnr

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
1nnr
Jmol
Contents
Protein chains
134 a.a. *
Ligands
SO4 ×2
Metals
_MN ×2
Waters ×90
* Residue conservation analysis
PDB id:
1nnr
Name: Transferase
Title: Crystal structure of a probable fosfomycin resistance protei from pseudomonas aeruginosa with sulfate present in the act
Structure: Probable fosfomycin resistance protein. Chain: a, b. Engineered: yes
Source: Pseudomonas aeruginosa. Organism_taxid: 208964. Strain: pao1. Gene: pa1129. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
2.25Å     R-factor:   0.197     R-free:   0.268
Authors: C.L.Rife,R.E.Pharris,M.E.Newcomer,R.N.Armstrong
Key ref:
R.E.Rigsby et al. (2004). Phosphonoformate: a minimal transition state analogue inhibitor of the fosfomycin resistance protein, FosA. Biochemistry, 43, 13666-13673. PubMed id: 15504029 DOI: 10.1021/bi048767h
Date:
14-Jan-03     Release date:   27-Jan-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q9I4K6  (FOSA_PSEAE) -  Glutathione transferase FosA
Seq:
Struc:
135 a.a.
134 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.5.1.18  - Glutathione transferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RX + glutathione = HX + R-S-glutathione
RX
+ glutathione
= HX
+ R-S-glutathione
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     metabolic process   2 terms 
  Biochemical function     transferase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1021/bi048767h Biochemistry 43:13666-13673 (2004)
PubMed id: 15504029  
 
 
Phosphonoformate: a minimal transition state analogue inhibitor of the fosfomycin resistance protein, FosA.
R.E.Rigsby, C.L.Rife, K.L.Fillgrove, M.E.Newcomer, R.N.Armstrong.
 
  ABSTRACT  
 
Fosfomycin [(1R,2S)-epoxypropylphosphonic acid] is a simple phosphonate found to have antibacterial activity against both Gram-positive and Gram-negative microorganisms. Early resistance to the clinical use of the antibiotic was linked to a plasmid-encoded resistance protein, FosA, that catalyzes the addition of glutathione to the oxirane ring, rendering the antibiotic inactive. Subsequent studies led to the discovery of a genomically encoded homologue in the pathogen Pseudomonas aeruginosa. The proteins are Mn(II)-dependent enzymes where the metal is proposed to act as a Lewis acid stabilizing the negative charge that develops on the oxirane oxygen in the transition state. Several simple phosphonates, including the antiviral compound phosphonoformate (K(i) = 0.4 +/- 0.1 microM, K(d) approximately 0.2 microM), are shown to be inhibitors of FosA. The crystal structure of FosA from P. aeruginosa with phosphonoformate bound in the active site has been determined at 0.95 A resolution and reveals that the inhibitor forms a five-coordinate complex with the Mn(II) center with a geometry similar to that proposed for the transition state of the reaction. Binding studies show that phosphonoformate has a near-diffusion-controlled on rate (k(on) approximately 10(7)-10(8) M(-1) s(-1)) and an off rate (k(off) = 5 s(-1)) that is slower than that for fosfomycin (k(off) = 30 s(-1)). Taken together, these data suggest that the FosA-catalyzed reaction has a very early transition state and phosphonoformate acts as a minimal transition state analogue inhibitor.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21212150 V.N.De Groote, M.Fauvart, C.I.Kint, N.Verstraeten, A.Jans, P.Cornelis, and J.Michiels (2011).
Pseudomonas aeruginosa fosfomycin resistance mechanisms affect non-inherited fluoroquinolone tolerance.
  J Med Microbiol, 60, 329-336.  
17855399 H.Cheng, B.H.Kim, and N.V.Grishin (2008).
MALISAM: a database of structurally analogous motifs in proteins.
  Nucleic Acids Res, 36, D211-D217.  
17537395 R.E.Rigsby, D.W.Brown, E.Dawson, T.P.Lybrand, and R.N.Armstrong (2007).
A model for glutathione binding and activation in the fosfomycin resistance protein, FosA.
  Arch Biochem Biophys, 464, 277-283.  
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