PDBsum entry 2fjn

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Hydrolase PDB id
Protein chains
289 a.a. *
073 ×2
_CL ×2
Waters ×367
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: The structure of phosphotyrosine phosphatase 1b in complex with compound 2
Structure: Tyrosine-protein phosphatase, non-receptor type 1. Chain: a, b. Fragment: catalytic domain (residues 1-298). Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn1, ptp1b. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.20Å     R-factor:   0.208     R-free:   0.244
Authors: E.Asante-Appiah,S.Patel,C.Desponts,J.M.Taylor,C.Lau, C.Dufresne,M.Therien,R.Friesen,J.W.Becker,Y.Leblanc, B.P.Kennedy,G.Scapin
Key ref:
E.Asante-Appiah et al. (2006). Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase. J Biol Chem, 281, 8010-8015. PubMed id: 16407290 DOI: 10.1074/jbc.M511827200
03-Jan-06     Release date:   17-Jan-06    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
435 a.a.
289 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 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.M511827200 J Biol Chem 281:8010-8015 (2006)
PubMed id: 16407290  
Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.
E.Asante-Appiah, S.Patel, C.Desponts, J.M.Taylor, C.Lau, C.Dufresne, M.Therien, R.Friesen, J.W.Becker, Y.Leblanc, B.P.Kennedy, G.Scapin.
PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu119 to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP-1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.
  Selected figure(s)  
Figure 1.
Chemical structures and IC[50]s for compound 1 and its analog, compound 2 (without the ester group), on PTP-1B and TCPTP.
Figure 2.
A, representation of compound 1 bound in WT PTP-1B binding site: red, P-loop or catalytic site (His^214-Arg^221); magenta, WPD loop (His^175-Pro^185), containing the catalytic Asp^181; yellow, YRD loop (Tyr^46-Asp^48); blue, secondary aryl binding site, including Arg^24 and Arg^254, as described by Puius et al. (16). The loop spanning residues 110-121 is colored according to atom type (C, green;N, blue;O, red;S, yellow); the residues that are different in PTP-1B and TCPTP are in orange. B, stereo-view of the overlay of compound 1 and the 110-121 loops in the two molecules present in the asymmetric unit (green and yellow). Although the conformation of the loops are somewhat different, they both assume a closed conformation (i.e. near the bound ligand), and the side chain of Leu^119 is in both molecules interacting with the ligand. The position of the same loop in 1PTY (magenta) is also displayed for comparison.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 8010-8015) 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.  
20725946 L.Gao, H.Sun, and S.Q.Yao (2010).
Activity-based high-throughput determination of PTPs substrate specificity using a phosphopeptide microarray.
  Biopolymers, 94, 810-819.  
18855890 M.L.Mohler, Y.He, Z.Wu, D.J.Hwang, and D.D.Miller (2009).
Recent and emerging anti-diabetes targets.
  Med Res Rev, 29, 125-195.  
19888762 M.R.Karver, D.Krishnamurthy, R.A.Kulkarni, N.Bottini, and A.M.Barrios (2009).
Identifying potent, selective protein tyrosine phosphatase inhibitors from a library of Au(I) complexes.
  J Med Chem, 52, 6912-6918.  
19622861 S.B.Patel, P.M.Cameron, S.J.O'Keefe, B.Frantz-Wattley, J.Thompson, E.A.O'Neill, T.Tennis, L.Liu, J.W.Becker, and G.Scapin (2009).
The three-dimensional structure of MAP kinase p38beta: different features of the ATP-binding site in p38beta compared with p38alpha.
  Acta Crystallogr D Biol Crystallogr, 65, 777-785.
PDB codes: 3gc7 3gc8 3gc9
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.  
17191286 M.Stuible, L.Zhao, I.Aubry, D.Schmidt-Arras, F.D.Böhmer, C.J.Li, and M.L.Tremblay (2007).
Cellular inhibition of protein tyrosine phosphatase 1B by uncharged thioxothiazolidinone derivatives.
  Chembiochem, 8, 179-186.  
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.