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Hydrolase PDB-id
1c86
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Description
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PROCHECK
Protein chain
296 a.a. *
Ligands
OPA
Waters ×128

* Residue conservation analysis
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PDB id: 1c86
Name: Hydrolase
Title: Crystal structure of protein tyrosine phosphatase 1b (r47v, d48n) complexed with 2-(oxalyl-amino-4,7-dihydro-5h- thieno[2,3-c]pyran-3-carboxylic acid

Structure:
Protein (protein-tyrosine phosphatase 1b). Chain: a. Synonym: ptp1b. Engineered: yes. Mutation: yes

Source:
Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

UniProt:
P18031 (PTN1_HUMAN) Pfam   ArchSchema ?
Seq:
Struc:
Seq: 435 a.a.
Struc: 296 a.a.*
Key:    PfamA domain  PfamB domain
 Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme class:
E.C.3.1.3.48   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:
Protein tyrosine phosphate + H2O = protein tyrosine + phosphate (see diagram below)

Resolution:
2.30Å

R-factor:
0.194

R-free:
0.262

Authors:
L.F.Iversen,H.S.Andersen,S.B.Mortensen,N.P.Moller

Key ref:
L.F.Iversen et al. (2000). Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B.. J Biol Chem, 275, 10300-10307. [PubMed id: 10744717] [DOI: 10.1074/jbc.275.14.10300]

Date:
16-Apr-00

Release date:
03-May-00

Related entries:
1ecv
ptp1b complexed with 5-iodo-2-(oxalyl-amino)-benzoic acid
1c83
ptp1b complexed with 6-(oxalyl-amino)-1h-indole-5-
carboxylic acid
1c84
ptp1b complexed with 3-(oxalyl-amino)-naphthalene-2-
carboxlic acid
1c85
ptp1b complexed with 2-(oxalyl-amino)-benzoic acid
... plus others (see Header records)
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Enzyme reaction for E.C.3.1.3.48


Protein tyrosine phosphate
+ H(2)O
=

protein tyrosine
Bound ligand (Het Group name = OPA)
matches with 40.00% similarity
+
phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site.

 
    Key reference    
 
 
DOI no: 10.1074/jbc.275.14.10300 J Biol Chem 275:10300-10307 (2000)
PubMed id: 10744717  
 
 
Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B.
L.F.Iversen, H.S.Andersen, S.Branner, S.B.Mortensen, G.H.Peters, K.Norris, O.H.Olsen, C.B.Jeppesen, B.F.Lundt, W.Ripka, K.B.Møller, N.P.Møller.
 
  ABSTRACT  
 
Several protein-tyrosine phosphatases (PTPs) have been proposed to act as negative regulators of insulin signaling. Recent studies have shown increased insulin sensitivity and resistance to obesity in PTP1B knockout mice, thus pointing to this enzyme as a potential drug target in diabetes. Structure-based design, guided by PTP mutants and x-ray protein crystallography, was used to optimize a relatively weak, nonphosphorus, nonpeptide general PTP inhibitor (2-(oxalyl-amino)-benzoic acid) into a highly selective PTP1B inhibitor. This was achieved by addressing residue 48 as a selectivity determining residue. By introducing a basic nitrogen in the core structure of the inhibitor, a salt bridge was formed to Asp-48 in PTP1B. In contrast, the basic nitrogen causes repulsion in other PTPs containing an asparagine in the equivalent position resulting in a remarkable selectivity for PTP1B. Importantly, this was accomplished while retaining the molecular weight of the inhibitor below 300 g/mol.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Chemical structures of OBA-1 and its derivatives.
Figure 4.
Fig. 4. Schematic representation of compound 5 in the active site pocket of PTP1B. Distances are in Å for noncovalent interactions between PTP1B and compound 5. Van der Waals interactions are illustrated by arcs. Nomenclature used for the different groups of compound 5.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2000, 275, 10300-10307) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
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.  
17183521 T.Sun, Q.Wang, Z.Yu, Y.Zhang, Y.Guo, K.Chen, X.Shen, and H.Jiang (2007).
Hyrtiosal, a PTP1B inhibitor from the marine sponge Hyrtios erectus, shows extensive cellular effects on PI3K/AKT activation, glucose transport, and TGFbeta/Smad2 signaling.
  Chembiochem, 8, 187-193.  
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
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
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.  
12789688 T.Honma (2003).
Recent advances in de novo design strategy for practical lead identification.
  Med Res Rev, 23, 606-632.  
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.  
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.  
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
12186556 H.Fu, J.Park, and D.Pei (2002).
Peptidyl aldehydes as reversible covalent inhibitors of protein tyrosine phosphatases.
  Biochemistry, 41, 10700-10709.  
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
11585896 J.N.Andersen, O.H.Mortensen, G.H.Peters, P.G.Drake, L.F.Iversen, O.H.Olsen, P.G.Jansen, H.S.Andersen, N.K.Tonks, and N.P.Møller (2001).
Structural and evolutionary relationships among protein tyrosine phosphatase domains.
  Mol Cell Biol, 21, 7117-7136.  
11568484 M.Balasubramanyam, and V.Mohan (2001).
Orally active insulin mimics: where do we stand now?
  J Biosci, 26, 383-390.  
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.