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PDBsum entry 1ecv

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Hydrolase PDB id
1ecv
Jmol
Contents
Protein chain
297 a.a. *
Ligands
ACT ×3
878
Waters ×241
* Residue conservation analysis
PDB id:
1ecv
Name: Hydrolase
Title: Crystal structure of protein tyrosine phosphatase 1b complexed with 5-iodo-2-(oxalyl-amino)-benzoic acid
Structure: Protein-tyrosine phosphatase 1b. Chain: a. Synonym: ptp1b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.95Å     R-factor:   0.194     R-free:   0.249
Authors: H.S.Andersen,L.F.Iversen,S.Branner,H.B.Rasmussen, N.P.H.Moller
Key ref:
H.S.Andersen et al. (2000). 2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases. J Biol Chem, 275, 7101-7108. PubMed id: 10702277 DOI: 10.1074/jbc.275.10.7101
Date:
26-Jan-00     Release date:   15-Mar-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
Seq:
Struc:
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.3.1.3.48  - Protein-tyrosine-phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protein tyrosine phosphate + H2O = protein tyrosine + phosphate
Protein tyrosine phosphate
+ H(2)O
=
protein tyrosine
Bound ligand (Het Group name = 878)
matches with 43.00% similarity
+ 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  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.275.10.7101 J Biol Chem 275:7101-7108 (2000)
PubMed id: 10702277  
 
 
2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases.
H.S.Andersen, L.F.Iversen, C.B.Jeppesen, S.Branner, K.Norris, H.B.Rasmussen, K.B.Møller, N.P.Møller.
 
  ABSTRACT  
 
Protein-tyrosine phosphatases (PTPs) are critically involved in regulation of signal transduction processes. Members of this class of enzymes are considered attractive therapeutic targets in several disease states, e.g. diabetes, cancer, and inflammation. However, most reported PTP inhibitors have been phosphorus-containing compounds, tight binding inhibitors, and/or inhibitors that covalently modify the enzymes. We therefore embarked on identifying a general, reversible, competitive PTP inhibitor that could be used as a common scaffold for lead optimization for specific PTPs. We here report the identification of 2-(oxalylamino)-benzoic acid (OBA) as a classical competitive inhibitor of several PTPs. X-ray crystallography of PTP1B complexed with OBA and related non-phosphate low molecular weight derivatives reveals that the binding mode of these molecules to a large extent mimics that of the natural substrate including hydrogen bonding to the PTP signature motif. In addition, binding of OBA to the active site of PTP1B creates a unique arrangement involving Asp(181), Lys(120), and Tyr(46). PTP inhibitors are essential tools in elucidating the biological function of specific PTPs and they may eventually be developed into selective drug candidates. The unique enzyme kinetic features and the low molecular weight of OBA makes it an ideal starting point for further optimization.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Structures of OBA and derivatives. 1, OBA; 2, 3-(oxalylamino)-naphthalene-2-carboxylic acid; 3, 6-(oxalylamino)-1H-indole-5-carboxylic acid; 4, 6-(oxalylamino)-1H-indole-7-carboxylic acid; 5, 5-iodo-2-(oxalylamino)-benzoic acid.
Figure 6.
Fig. 6. o-Carboxy group interactions. A, identical protein atoms in the Tyr(P)·C215S PTP1B complex and the compound 1·PTP1B complex are superimposed. The Tyr(P) is in orange, the Tyr(P)/C215S PTP1B protein is in red, compound 1 is in white, and the PTP1B protein interacting with compound 1 is in yellow. B, the hydrogen bonding network around the o-carboxy group of compound 1; atoms are colored according to atom type (carbon in white, oxygen in red, nitrogen in blue, and iodine in green). Hydrogen bonding lengths are given in Å.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2000, 275, 7101-7108) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21453996 J.J.Ramírez-Espinosa, M.Y.Rios, S.López-Martínez, F.López-Vallejo, J.L.Medina-Franco, P.Paoli, G.Camici, G.Navarrete-Vázquez, R.Ortiz-Andrade, and S.Estrada-Soto (2011).
Antidiabetic activity of some pentacyclic acid triterpenoids, role of PTP-1B: in vitro, in silico, and in vivo approaches.
  Eur J Med Chem, 46, 2243-2251.  
20727982 C.Abad-Zapatero, O.Perišić, J.Wass, A.P.Bento, J.Overington, B.Al-Lazikani, and M.E.Johnson (2010).
Ligand efficiency indices for an effective mapping of chemico-biological space: the concept of an atlas-like representation.
  Drug Discov Today, 15, 804-811.  
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.  
18678493 X.Y.Zhang, V.L.Chen, M.S.Rosen, E.R.Blair, A.M.Lone, and A.C.Bishop (2008).
Allele-specific inhibition of divergent protein tyrosine phosphatases with a single small molecule.
  Bioorg Med Chem, 16, 8090-8097.  
17532515 A.C.Bishop, X.Y.Zhang, and A.M.Lone (2007).
Generation of inhibitor-sensitive protein tyrosine phosphatases via active-site mutations.
  Methods, 42, 278-288.  
17437721 C.Grundner, D.Perrin, R.Hooft van Huijsduijnen, D.Swinnen, J.Gonzalez, C.L.Gee, T.N.Wells, and T.Alber (2007).
Structural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB.
  Structure, 15, 499-509.
PDB code: 2oz5
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.  
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.  
17039461 S.Lee, and Q.Wang (2007).
Recent development of small molecular specific inhibitor of protein tyrosine phosphatase 1B.
  Med Res Rev, 27, 553-573.  
17139078 A.G.Evdokimov, M.Pokross, R.Walter, M.Mekel, B.Cox, C.Li, R.Bechard, F.Genbauffe, R.Andrews, C.Diven, B.Howard, V.Rastogi, J.Gray, M.Maier, and K.G.Peters (2006).
Engineering the catalytic domain of human protein tyrosine phosphatase beta for structure-based drug discovery.
  Acta Crystallogr D Biol Crystallogr, 62, 1435-1445.
PDB codes: 2hc1 2hc2 2i3r 2i3u 2i4e 2i4g 2i4h 2i5x
15937284 M.S.Willis, J.K.Hogan, P.Prabhakar, X.Liu, K.Tsai, Y.Wei, and T.Fox (2005).
Investigation of protein refolding using a fractional factorial screen: a study of reagent effects and interactions.
  Protein Sci, 14, 1818-1826.  
16013076 U.Schieborr, M.Vogtherr, B.Elshorst, M.Betz, S.Grimme, B.Pescatore, T.Langer, K.Saxena, and H.Schwalbe (2005).
How much NMR data is required to determine a protein-ligand complex structure?
  Chembiochem, 6, 1891-1898.  
15333922 A.K.Pedersen, G.H.Peters G, K.B.Møller, L.F.Iversen, and J.S.Kastrup (2004).
Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B.
  Acta Crystallogr D Biol Crystallogr, 60, 1527-1534.
PDB code: 1sug
15258570 C.Wiesmann, K.J.Barr, J.Kung, J.Zhu, D.A.Erlanson, W.Shen, B.J.Fahr, M.Zhong, L.Taylor, M.Randal, R.S.McDowell, and S.K.Hansen (2004).
Allosteric inhibition of protein tyrosine phosphatase 1B.
  Nat Struct Mol Biol, 11, 730-737.
PDB codes: 1t48 1t49 1t4j
15013940 S.D.Taylor, and B.Hill (2004).
Recent advances in protein tyrosine phosphatase 1B inhibitors.
  Expert Opin Investig Drugs, 13, 199-214.  
14517908 A.Nayeem, S.Krystek, and T.Stouch (2003).
An assessment of protein-ligand binding site polarizability.
  Biopolymers, 70, 201-211.  
12668436 T.M.Frimurer, G.H.Peters, L.F.Iversen, H.S.Andersen, N.P.Møller, and O.H.Olsen (2003).
Ligand-induced conformational changes: improved predictions of ligand binding conformations and affinities.
  Biophys J, 84, 2273-2281.  
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.  
11807171 Z.Y.Zhang (2002).
Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development.
  Annu Rev Pharmacol Toxicol, 42, 209-234.  
11468356 G.Scapin, S.Patel, V.Patel, B.Kennedy, and E.Asante-Appiah (2001).
The structure of apo protein-tyrosine phosphatase 1B C215S mutant: more than just an S --> O change.
  Protein Sci, 10, 1596-1605.
PDB code: 1i57
11568484 M.Balasubramanyam, and V.Mohan (2001).
Orally active insulin mimics: where do we stand now?
  J Biosci, 26, 383-390.  
11459664 Y.T.Chen, M.B.Onaran, C.J.Doss, and C.T.Seto (2001).
alpha-Ketocarboxylic acid-based inhibitors of protein tyrosine phosphatases.
  Bioorg Med Chem Lett, 11, 1935-1938.  
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.