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PDBsum entry 1pa9

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Hydrolase PDB id
1pa9
Jmol
Contents
Protein chain
279 a.a. *
Ligands
CSN
Waters ×217
* Residue conservation analysis
PDB id:
1pa9
Name: Hydrolase
Title: Yersinia protein-tyrosine phosphatase complexed with pncs (yop51,pasteurella x,ptpase,yop51delta162) (catalytic domain, residues 163-468) mutant with cys 235 replaced by arg (c235r)
Structure: Protein-tyrosine phosphatase yoph. Chain: a. Fragment: catalytic domain. Synonym: virulence protein. Engineered: yes. Mutation: yes
Source: Yersinia enterocolitica. Organism_taxid: 630. Gene: yoph or yop51. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.00Å     R-factor:   0.226     R-free:   0.243
Authors: J.P.Sun,L.Wu,A.A.Fedorov,S.C.Almo,Z.Y.Zhang
Key ref:
J.P.Sun et al. (2003). Crystal structure of the Yersinia protein-tyrosine phosphatase YopH complexed with a specific small molecule inhibitor. J Biol Chem, 278, 33392-33399. PubMed id: 12810712 DOI: 10.1074/jbc.M304693200
Date:
13-May-03     Release date:   04-Nov-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P15273  (YOPH_YEREN) -  Tyrosine-protein phosphatase YopH
Seq:
Struc:
468 a.a.
279 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.1.3.48  - Protein-tyrosine-phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protein tyrosine phosphate + H2O = protein tyrosine + phosphate
Protein tyrosine phosphate
+ H(2)O
= protein tyrosine
+ phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     dephosphorylation   2 terms 
  Biochemical function     phosphatase activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M304693200 J Biol Chem 278:33392-33399 (2003)
PubMed id: 12810712  
 
 
Crystal structure of the Yersinia protein-tyrosine phosphatase YopH complexed with a specific small molecule inhibitor.
J.P.Sun, L.Wu, A.A.Fedorov, S.C.Almo, Z.Y.Zhang.
 
  ABSTRACT  
 
The pathogenic bacteria Yersinia are causative agents in human diseases ranging from gastrointestinal syndromes to bubonic plague. There is increasing risk of misuse of infectious agents, such as Yersinia pestis, as weapons of terror as well as instruments of warfare for mass destruction. Because the phosphatase activity of the Yersinia protein tyrosine phosphatase, YopH, is essential for virulence in the Yersinia pathogen, potent and selective YopH inhibitors are expected to serve as novel anti-plague agents. We have identified a specific YopH small molecule inhibitor, p-nitrocatechol sulfate (pNCS), which exhibits a Ki value of 25 microM for YopH and displays a 13-60-fold selectivity in favor of YopH against a panel of mammalian PTPs. To facilitate the understanding of the underlying molecular basis for tight binding and specificity, we have determined the crystal structure of YopH in complex with pNCS at a 2.0-A resolution. The structural data are corroborated by results from kinetic analyses of the interactions of YopH and its site-directed mutants with pNCS. The results show that while the interactions of the sulfuryl moiety and the phenyl ring with the YopH active site contribute to pNCS binding affinity, additional interactions of the hydroxyl and nitro groups in pNCS with Asp-356, Gln-357, Arg-404, and Gln-446 are responsible for the increased potency and selectivity. In particular, we note that residues Arg-404, Glu-290, Asp-356, and a bound water (WAT185) participate in a unique H-bonding network with the hydroxyl group ortho to the sulfuryl moiety, which may be exploited to design more potent and specific YopH inhibitors.
 
  Selected figure(s)  
 
Figure 2.
FIG. 2. The structure of YopH with pNCS bound. A, simulated annealing omit map showing unbiased density for pNCS. The density shown is a F[o] - F[c] map contoured at 3.2 with the refined models of the inhibitor and YopH superimposed. This figure was generated using SETOR (50). B, GRASP (51) surface representation of YopH in complex with pNCS. The blue, white, and red shadings represent positively charged (+40 kT), neutral, and negatively charged (-40 kT) surface regions, respectively. pNCS is depicted according to atom type (O, pink; N, dark blue; C, white; and S, green).
Figure 4.
FIG. 4. Interactions between pNCS and YopH. A, H-bonding and polar interactions with a cutoff distance of 3.2 Å for hydrogen bonds and 4.0 Å for electrostatic or polar interactions. B, hydrophobic interactions with a cutoff distance of 4.5 Å.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 33392-33399) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
18081726 J.E.Trosky, A.D.Liverman, and K.Orth (2008).
Yersinia outer proteins: Yops.
  Cell Microbiol, 10, 557-565.  
18528979 S.Liu, B.Zhou, H.Yang, Y.He, Z.X.Jiang, S.Kumar, L.Wu, and Z.Y.Zhang (2008).
Aryl vinyl sulfonates and sulfones as active site-directed and mechanism-based probes for protein tyrosine phosphatases.
  J Am Chem Soc, 130, 8251-8260.
PDB codes: 3blt 3blu 3bm8
17505108 J.Phan, J.E.Tropea, and D.S.Waugh (2007).
Structure-assisted discovery of Variola major H1 phosphatase inhibitors.
  Acta Crystallogr D Biol Crystallogr, 63, 698-704.
PDB code: 2p4d
17766352 Z.Huang, and C.F.Wong (2007).
A mining minima approach to exploring the docking pathways of p-nitrocatechol sulfate to YopH.
  Biophys J, 93, 4141-4150.  
16098211 C.E.Stebbins (2005).
Structural microbiology at the pathogen-host interface.
  Cell Microbiol, 7, 1227-1236.  
16271885 C.Grundner, H.L.Ng, and T.Alber (2005).
Mycobacterium tuberculosis protein tyrosine phosphatase PtpB structure reveals a diverged fold and a buried active site.
  Structure, 13, 1625-1634.
PDB code: 1ywf
16142916 K.L.Tran, P.A.Aronov, H.Tanaka, J.W.Newman, B.D.Hammock, and C.Morisseau (2005).
Lipid sulfates and sulfonates are allosteric competitive inhibitors of the N-terminal phosphatase activity of the mammalian soluble epoxide hydrolase.
  Biochemistry, 44, 12179-12187.  
15670918 X.Hu, and C.E.Stebbins (2005).
Molecular docking and 3D-QSAR studies of Yersinia protein tyrosine phosphatase YopH inhibitors.
  Bioorg Med Chem, 13, 1101-1109.  
15093830 H.Remaut, and G.Waksman (2004).
Structural biology of bacterial pathogenesis.
  Curr Opin Struct Biol, 14, 161-170.  
15148367 S.Kumar, B.Zhou, F.Liang, W.Q.Wang, Z.Huang, and Z.Y.Zhang (2004).
Activity-based probes for protein tyrosine phosphatases.
  Proc Natl Acad Sci U S A, 101, 7943-7948.  
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.

 

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