PDBsum entry 1lqf

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Hydrolase PDB id
Protein chains
287 a.a. *
BGD ×4
Waters ×528
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Structure of ptp1b in complex with a peptidic bisphosphonate inhibitor
Structure: Protein-tyrosine phosphatase, non-receptor type 1. Chain: a, b, c, d. Fragment: catalytic domain (residues 1-283). Synonym: ptp1b, protein tyrosine phosphatase 1b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.50Å     R-factor:   0.228     R-free:   0.286
Authors: E.Asante-Appiah,S.Patel,C.Dufresne,G.Scapin
Key ref:
E.Asante-Appiah et al. (2002). The structure of PTP-1B in complex with a peptide inhibitor reveals an alternative binding mode for bisphosphonates. Biochemistry, 41, 9043-9051. PubMed id: 12119018 DOI: 10.1021/bi0259554
10-May-02     Release date:   24-Jul-02    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
435 a.a.
287 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: 10.1021/bi0259554 Biochemistry 41:9043-9051 (2002)
PubMed id: 12119018  
The structure of PTP-1B in complex with a peptide inhibitor reveals an alternative binding mode for bisphosphonates.
E.Asante-Appiah, S.Patel, C.Dufresne, P.Roy, Q.Wang, V.Patel, R.W.Friesen, C.Ramachandran, J.W.Becker, Y.Leblanc, B.P.Kennedy, G.Scapin.
Inhibitors of PTP-1B could be therapeutically beneficial in the treatment of type 2 diabetes. Owing to the large number of phosphatases in the cell, inhibitors against PTP-1B must not only be potent but selective as well. N-Benzoyl-L-glutamyl-[4-phosphono(difluoromethyl)]-L-phenylalanine-[4-phosphono(difluoro-methyl)]-L-phenylalanineamide (BzN-EJJ-amide) is a low nanomolar inhibitor of PTP-1B that shows selectivity over several protein tyrosine phosphatases. To gain an insight into the basis of its potency and selectivity, we evaluated several analogues of the inhibitor and introduced amino acid substitutions into PTP-1B by site-directed mutagenesis. We also determined the crystal structure of PTP-1B in complex with BzN-EJJ-amide at 2.5 A resolution. Our results indicate that the high inhibitory potency is due to interactions of several of its chemical groups with specific protein residues. An interaction between BzN-EJJ-amide and Asp48 is of particular significance, as substitution of Asp48 to alanine resulted in a 100-fold loss in potency. The crystal structure also revealed an unexpected binding orientation for a bisphosphonate inhibitor on PTP-1B, where the second difluorophosphonomethyl phenylalanine (F(2)PMP) moiety is bound close to Arg47 rather than in the previously identified second aryl phosphate site demarked by Arg24 and Arg254. Our results suggest that potent and selective PTP-1B inhibitors may be designed by targeting the region containing Arg47 and Asp48.

Literature references that cite this PDB file's key reference

  PubMed id Reference
17046267 J.Xie, and C.T.Seto (2007).
A two stage click-based library of protein tyrosine phosphatase inhibitors.
  Bioorg Med Chem, 15, 458-473.  
16407290 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, and G.Scapin (2006).
Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.
  J Biol Chem, 281, 8010-8015.
PDB codes: 2fjm 2fjn
16916797 P.J.Ala, L.Gonneville, M.C.Hillman, M.Becker-Pasha, M.Wei, B.G.Reid, R.Klabe, E.W.Yue, B.Wayland, B.Douty, P.Polam, Z.Wasserman, M.Bower, A.P.Combs, T.C.Burn, G.F.Hollis, and R.Wynn (2006).
Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.
  J Biol Chem, 281, 32784-32795.
PDB codes: 2cm2 2cm3 2cm7 2cm8 2cma 2cmb 2cmc
15900534 L.Bialy, and H.Waldmann (2005).
Inhibitors of protein tyrosine phosphatases: next-generation drugs?
  Angew Chem Int Ed Engl, 44, 3814-3839.  
15013940 S.D.Taylor, and B.Hill (2004).
Recent advances in protein tyrosine phosphatase 1B inhibitors.
  Expert Opin Investig Drugs, 13, 199-214.  
14722096 Y.Romsicki, M.Reece, J.Y.Gauthier, E.Asante-Appiah, and B.P.Kennedy (2004).
Protein tyrosine phosphatase-1B dephosphorylation of the insulin receptor occurs in a perinuclear endosome compartment in human embryonic kidney 293 cells.
  J Biol Chem, 279, 12868-12875.  
12547827 J.P.Sun, A.A.Fedorov, S.Y.Lee, X.L.Guo, K.Shen, D.S.Lawrence, S.C.Almo, and Z.Y.Zhang (2003).
Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor.
  J Biol Chem, 278, 12406-12414.
PDB codes: 1n6w 1pxh
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