PDBsum entry 1kav

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Hydrolase PDB id
Protein chain
297 a.a. *
Waters ×133
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Human tyrosine phosphatase 1b complexed with an inhibitor
Structure: Protein-tyrosine phosphatase, non-receptor type 1. Chain: a. Synonym: protein-tyrosine phosphatase 1b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
2.35Å     R-factor:   0.200     R-free:   0.250
Authors: Z.Jia,Q.Ye,A.N.Dinaut,Q.Wang,D.Waddleton,P.Payette, C.Ramachandran,B.Kennedy,G.Hum,S.D.Taylor
Key ref: Z.Jia et al. (2001). Structure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimetics. J Med Chem, 44, 4584-4594. PubMed id: 11741477 DOI: 10.1021/jm010266w
03-Nov-01     Release date:   19-Jun-02    
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Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
435 a.a.
297 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/jm010266w J Med Chem 44:4584-4594 (2001)
PubMed id: 11741477  
Structure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimetics.
Z.Jia, Q.Ye, A.N.Dinaut, Q.Wang, D.Waddleton, P.Payette, C.Ramachandran, B.Kennedy, G.Hum, S.D.Taylor.
Protein tyrosine phosphatases (PTPases) are signal-transducing enzymes that dephosphorylate intracellular proteins that have phosphorylated tyrosine residues. It has been demonstrated that protein tyrosine phosphatase 1B (PTP1B) is an attractive therapeutic target because of its involvement in regulating insulin sensitivity (Elcheby et al. Science 1999, 283, 1544-1548). The identification of a second binding site in PTP1B (Puius et al., Proc. Natl. Acad. Sci. U.S.A.1997, 94, 13420-13425) suggests a new strategy for inhibitor design, where appropriate compounds may be made to simultaneously occupy both binding sites to gain much higher affinity and selectivity. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have determined the crystal structure of PTP1B complexed with two non-peptidyl inhibitors, 4 and 5, both of which contain two aryl difluoromethylenephosphonic acid groups, a nonhydrolyzable phosphate mimetic. The structures were determined and refined to 2.35 and 2.50 A resolution, respectively. Although one of the inhibitors seems to have satisfied the perceived requirement for dual binding, it did not bind both the active site and the adjacent noncatalytic binding site as expected. The second or distal phosphonate group instead extends into the solvent and makes water-mediated interactions with Arg-47. The selectivity of the more potent of these two inhibitors, as well as four other inhibitors bearing two such phosphate mimetics for PTP1B versus seven other PTPases, was examined. In general, selectivity was modest to good when compared to PTPases Cdc25a, PTPmeg-1, PTPbeta, and CD45. However, selectivity was generally poor when compared to other PTPases such as SHP-1, SHP-2, and especially TCPTP, for which almost no selectivity was found. The implications these results have concerning the utility of dual-binding inhibitors are discussed.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20490879 J.P.Yesudas, F.B.Sayyed, and C.H.Suresh (2011).
Analysis of structural water and CH···π interactions in HIV-1 protease and PTP1B complexes using a hydrogen bond prediction tool, HBPredicT.
  J Mol Model, 17, 401-413.  
21425288 S.Bruckner, and S.Boresch (2011).
Efficiency of alchemical free energy simulations. I. A practical comparison of the exponential formula, thermodynamic integration, and Bennett's acceptance ratio method.
  J Comput Chem, 32, 1303-1319.  
16364216 G.X.Liu, J.Z.Tan, C.Y.Niu, J.H.Shen, X.M.Luo, X.Shen, K.X.Chen, and H.L.Jiang (2006).
Molecular dynamics simulations of interaction between protein-tyrosine phosphatase 1B and a bidentate inhibitor.
  Acta Pharmacol Sin, 27, 100-110.  
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.  
15024017 I.K.Lund, H.S.Andersen, L.F.Iversen, O.H.Olsen, K.B.Møller, A.K.Pedersen, Y.Ge, D.D.Holsworth, M.J.Newman, F.U.Axe, and N.P.Møller (2004).
Structure-based design of selective and potent inhibitors of protein-tyrosine phosphatase beta.
  J Biol Chem, 279, 24226-24235.  
15013940 S.D.Taylor, and B.Hill (2004).
Recent advances in protein tyrosine phosphatase 1B inhibitors.
  Expert Opin Investig Drugs, 13, 199-214.  
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
12119018 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, and G.Scapin (2002).
The structure of PTP-1B in complex with a peptide inhibitor reveals an alternative binding mode for bisphosphonates.
  Biochemistry, 41, 9043-9051.
PDB code: 1lqf
12209150 T.O.Johnson, J.Ermolieff, and M.R.Jirousek (2002).
Protein tyrosine phosphatase 1B inhibitors for diabetes.
  Nat Rev Drug Discov, 1, 696-709.  
12237455 X.Espanel, M.Huguenin-Reggiani, and R.H.Van Huijsduijnen (2002).
The SPOT technique as a tool for studying protein tyrosine phosphatase substrate specificities.
  Protein Sci, 11, 2326-2334.  
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