PDBsum entry 1l8g

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Hydrolase PDB id
Protein chain
297 a.a. *
Waters ×136
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of ptp1b complexed with 7-(1,1-dioxo-1h- benzo[d]isothiazol-3-yloxymethyl)-2-(oxalyl-amino)-4,7- dihydro-5h-thieno[2,3-c]pyran-3-carboxylic acid
Structure: Protein-tyrosine phosphatase, non-receptor type 1. Chain: a. Synonym: ptp1b, protein-tyrosine phosphatase 1b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
2.50Å     R-factor:   0.189     R-free:   0.270
Authors: L.F.Iversen,H.S.Andersen,K.B.Moller,O.H.Olsen,G.H.Peters, S.Branner,S.B.Mortensen,T.K.Hansen,J.Lau,Y.Ge,D.D.Holsworth M.J.Newman,N.P.H.Moller
Key ref:
L.F.Iversen et al. (2001). Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases. Biochemistry, 40, 14812-14820. PubMed id: 11732900 DOI: 10.1021/bi011389l
20-Mar-02     Release date:   08-May-02    
Go to PROCHECK summary

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
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 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/bi011389l Biochemistry 40:14812-14820 (2001)
PubMed id: 11732900  
Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases.
L.F.Iversen, H.S.Andersen, K.B.Møller, O.H.Olsen, G.H.Peters, S.Branner, S.B.Mortensen, T.K.Hansen, J.Lau, Y.Ge, D.D.Holsworth, M.J.Newman, N.P.Hundahl Møller.
Utilizing structure-based design, we have previously demonstrated that it is possible to obtain selective inhibitors of protein-tyrosine phosphatase 1B (PTP1B). A basic nitrogen was introduced into a general PTP inhibitor to form a salt bridge to Asp48 in PTP1B and simultaneously cause repulsion in PTPs containing an asparagine in the equivalent position [Iversen, L. F., et al. (2000) J. Biol. Chem. 275, 10300-10307]. Further, we have recently demonstrated that Gly259 in PTP1B forms the bottom of a gateway that allows easy access to the active site for a broad range of substrates, while bulky residues in the same position in other PTPs cause steric hindrance and reduced substrate recognition capacity [Peters, G. H., et al. (2000) J. Biol. Chem. 275, 18201-18209]. The current study was undertaken to investigate the feasibility of structure-based design, utilizing these differences in accessibility to the active site among various PTPs. We show that a general, low-molecular weight PTP inhibitor can be developed into a highly selective inhibitor for PTP1B and TC-PTP by introducing a substituent, which is designed to address the region around residues 258 and 259. Detailed enzyme kinetic analysis with a set of wild-type and mutant PTPs, X-ray protein crystallography, and molecular modeling studies confirmed that selectivity for PTP1B and TC-PTP was achieved due to steric hindrance imposed by bulky position 259 residues in other PTPs.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20191319 Y.Huang, and A.Dömling (2011).
The Gewald multicomponent reaction.
  Mol Divers, 15, 3.  
19810703 D.Vidović, and S.C.Schürer (2009).
Knowledge-based characterization of similarity relationships in the human protein-tyrosine phosphatase family for rational inhibitor design.
  J Med Chem, 52, 6649-6659.  
19380334 J.F.Wang, K.Gong, D.Q.Wei, Y.X.Li, and K.C.Chou (2009).
Molecular dynamics studies on the interactions of PTP1B with inhibitors: from the first phosphate-binding site to the second one.
  Protein Eng Des Sel, 22, 349-355.  
18480264 K.Hellmuth, S.Grosskopf, C.T.Lum, M.Würtele, N.Röder, J.P.von Kries, M.Rosario, J.Rademann, and W.Birchmeier (2008).
Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking.
  Proc Natl Acad Sci U S A, 105, 7275-7280.  
17135270 K.M.Picha, S.S.Patel, S.Mandiyan, J.Koehn, and L.P.Wennogle (2007).
The role of the C-terminal domain of protein tyrosine phosphatase-1B in phosphatase activity and substrate binding.
  J Biol Chem, 282, 2911-2917.  
16534812 A.J.Barr, J.E.Debreczeni, J.Eswaran, and S.Knapp (2006).
Crystal structure of human protein tyrosine phosphatase 14 (PTPN14) at 1.65-A resolution.
  Proteins, 63, 1132-1136.
PDB code: 2bzl
16919785 A.J.Barr, and S.Knapp (2006).
MAPK-specific tyrosine phosphatases: new targets for drug discovery?
  Trends Pharmacol Sci, 27, 525-530.  
17008719 D.Tolkatchev, R.Shaykhutdinov, P.Xu, J.Plamondon, D.C.Watson, N.M.Young, and F.Ni (2006).
Three-dimensional structure and ligand interactions of the low molecular weight protein tyrosine phosphatase from Campylobacter jejuni.
  Protein Sci, 15, 2381-2394.
PDB code: 2gi4
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.  
16672235 J.Eswaran, J.E.Debreczeni, E.Longman, A.J.Barr, and S.Knapp (2006).
The crystal structure of human receptor protein tyrosine phosphatase kappa phosphatase domain 1.
  Protein Sci, 15, 1500-1505.
PDB codes: 2a3k 2c7s
16477622 M.Nayal, and B.Honig (2006).
On the nature of cavities on protein surfaces: application to the identification of drug-binding sites.
  Proteins, 63, 892-906.  
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
12556216 Z.Y.Zhang, and S.Y.Lee (2003).
PTP1B inhibitors as potential therapeutics in the treatment of type 2 diabetes and obesity.
  Expert Opin Investig Drugs, 12, 223-233.  
11907034 L.F.Iversen, K.B.Moller, A.K.Pedersen, G.H.Peters, A.S.Petersen, H.S.Andersen, S.Branner, S.B.Mortensen, and N.P.Moller (2002).
Structure determination of T cell protein-tyrosine phosphatase.
  J Biol Chem, 277, 19982-19990.
PDB code: 1l8k
12413557 P.Kuhn, K.Wilson, M.G.Patch, and R.C.Stevens (2002).
The genesis of high-throughput structure-based drug discovery using protein crystallography.
  Curr Opin Chem Biol, 6, 704-710.  
12546953 S.F.Betz, S.M.Baxter, and J.S.Fetrow (2002).
Function first: a powerful approach to post-genomic drug discovery.
  Drug Discov Today, 7, 865-871.  
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.  
12193602 X.L.Guo, K.Shen, F.Wang, D.S.Lawrence, and Z.Y.Zhang (2002).
Probing the molecular basis for potent and selective protein-tyrosine phosphatase 1B inhibition.
  J Biol Chem, 277, 41014-41022.  
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 code is shown on the right.