PDBsum entry 2f6f

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protein metals links
Hydrolase PDB id
Protein chain
302 a.a. *
_MG ×2
_CL ×3
Waters ×251
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: The structure of the s295f mutant of human ptp1b
Structure: Tyrosine-protein phosphatase, non-receptor type 1. Chain: a. Fragment: catalytic domain. Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn1, ptp1b. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.00Å     R-factor:   0.186     R-free:   0.203
Authors: J.Montalibet,K.Skorey,D.Mckay,G.Scapin,E.Asante-Appiah, B.P.Kennedy
Key ref:
J.Montalibet et al. (2006). Residues distant from the active site influence protein-tyrosine phosphatase 1B inhibitor binding. J Biol Chem, 281, 5258-5266. PubMed id: 16332678 DOI: 10.1074/jbc.M511546200
29-Nov-05     Release date:   06-Dec-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
435 a.a.
302 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - 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  


DOI no: 10.1074/jbc.M511546200 J Biol Chem 281:5258-5266 (2006)
PubMed id: 16332678  
Residues distant from the active site influence protein-tyrosine phosphatase 1B inhibitor binding.
J.Montalibet, K.Skorey, D.McKay, G.Scapin, E.Asante-Appiah, B.P.Kennedy.
Regions of protein-tyrosine phosphatase (PTP) 1B that are distant from the active site yet affect inhibitor binding were identified by a novel library screen. This screen was based on the observation that expression of v-Src in yeast leads to lethality, which can be rescued by the coexpression of PTP1B. However, this rescue is lost when yeast are grown in the presence of PTP1B inhibitors. To identify regions of PTP1B (amino acids 1-400, catalytic domain plus 80-amino acid C-terminal tail) that can affect the binding of the difluoromethyl phosphonate (DFMP) inhibitor 7-bromo-6-difluoromethylphosphonate 3-naphthalenenitrile, a library coexpressing PTP1B mutants and v-Src was generated, and the ability of yeast to grow in the presence of the inhibitor was evaluated. PTP1B inhibitor-resistant mutations were found to concentrate on helix alpha7 and its surrounding region, but not in the active site. No resistant amino acid substitutions were found to occur in the C-terminal tail, suggesting that this region has little effect on active-site inhibitor binding. An in-depth characterization of a resistant substitution localizing to region alpha7 (S295F) revealed that this change minimally affected enzyme catalytic activity, but significantly reduced the potency of a panel of structurally diverse DFMP PTP1B inhibitors. This loss of inhibitor potency was found to be due to the difluoro moiety of these inhibitors because only the difluoro inhibitors were shifted. For example, the inhibitor potency of a monofluorinated or non-fluorinated analog of one of these DFMP inhibitors was only minimally affected. Using this type of library screen, which can scan the nearly full-length PTP1B sequence (catalytic domain and C-terminal tail) for effects on inhibitor binding, we have been able to identify novel regions of PTP1B that specifically affect the binding of DFMP inhibitors.
  Selected figure(s)  
Figure 1.
FIGURE 1. Modeling of Inhibitor 1 into the PTP1B active site. The structure of Inhibitor 1 is shown in the inset. The active-site nucleophile Cys^215 in the PTP loop (pink) is shown along with Phe^182 in the WPD loop (green). Inhibitor 1 sits in the active site with the phosphonate (red) interacting with the PTP loop, and the difluoro group is within van der Waals distance of the phenyl side chain of Phe^182.
Figure 5.
FIGURE 5. Interactions of helix 7 with the PTP1B core. In the wild-type structure (Protein Data Bank code 1SUG; shown in cyan), an extensive network of hydrogen bonds connects helix 7 to helix 3 and the loop between strands 9 and 10. In the S295F mutant (shown in yellow), helix 7 is repositioned and partially disordered, with consequent disruption of this extensive network of interactions. Only the hydrogen bond between the side chains of Tyr^152 and Asn^193 is retained.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 5258-5266) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21179176 S.G.Julien, N.Dubé, S.Hardy, and M.L.Tremblay (2011).
Inside the human cancer tyrosine phosphatome.
  Nat Rev Cancer, 11, 35-49.  
20572251 B.Townshend, I.Aubry, R.C.Marcellus, K.Gehring, and M.L.Tremblay (2010).
An RNA aptamer that selectively inhibits the enzymatic activity of protein tyrosine phosphatase 1B in vitro.
  Chembiochem, 11, 1583-1593.  
18685809 K.Bharatham, N.Bharatham, Y.J.Kwon, and K.W.Lee (2008).
Molecular dynamics simulation study of PTP1B with allosteric inhibitor and its application in receptor based pharmacophore modeling.
  J Comput Aided Mol Des, 22, 925-933.  
18298793 L.Tabernero, A.R.Aricescu, E.Y.Jones, and S.E.Szedlacsek (2008).
Protein tyrosine phosphatases: structure-function relationships.
  FEBS J, 275, 867-882.  
17259984 S.G.Julien, N.Dubé, M.Read, J.Penney, M.Paquet, Y.Han, B.P.Kennedy, W.J.Muller, and M.L.Tremblay (2007).
Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis.
  Nat Genet, 39, 338-346.  
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.