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PDBsum entry 1q6s

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
1q6s
Jmol
Contents
Protein chains
289 a.a. *
Ligands
214 ×2
MPD
Metals
_CL ×3
_MG ×2
Waters ×396
* Residue conservation analysis
PDB id:
1q6s
Name: Hydrolase
Title: The structure of phosphotyrosine phosphatase 1b in complex with compound 9
Structure: Protein-tyrosine phosphatase, non-receptor type 1. Chain: a, b. Fragment: catalytic domain. Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn1 or ptp1b. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.20Å     R-factor:   0.196     R-free:   0.233
Authors: G.Scapin,S.B.Patel,J.W.Becker,Q.Wang,C.Desponts,D.Waddleton, K.Skorey,W.Cromlish,C.Bayly,M.Therien,J.Y.Gauthier,C.S.Li, C.K.Lau,C.Ramachandran,B.P.Kennedy,E.Asante-Appiah
Key ref:
G.Scapin et al. (2003). The structural basis for the selectivity of benzotriazole inhibitors of PTP1B. Biochemistry, 42, 11451-11459. PubMed id: 14516196 DOI: 10.1021/bi035098j
Date:
13-Aug-03     Release date:   30-Sep-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
Seq:
Struc:
435 a.a.
289 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 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
+ 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: 10.1021/bi035098j Biochemistry 42:11451-11459 (2003)
PubMed id: 14516196  
 
 
The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.
G.Scapin, S.B.Patel, J.W.Becker, Q.Wang, C.Desponts, D.Waddleton, K.Skorey, W.Cromlish, C.Bayly, M.Therien, J.Y.Gauthier, C.S.Li, C.K.Lau, C.Ramachandran, B.P.Kennedy, E.Asante-Appiah.
 
  ABSTRACT  
 
Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21283550 C.Tuzmen, and B.Erman (2011).
Identification of ligand binding sites of proteins using the gaussian network model.
  PLoS One, 6, e16474.  
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.  
20572251 B.Townshend, I.Aubry, R.C.Marcellus, K.Gehring, and M.L.Tremblay (2010).
An RNA aptamer that selectively inhibits the enzymatic activity of protein tyrosine phosphatase 1B in vitro.
  Chembiochem, 11, 1583-1593.  
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.  
  20944214 G.W.Han, C.Bakolitsa, M.D.Miller, A.Kumar, D.Carlton, R.J.Najmanovich, P.Abdubek, T.Astakhova, H.L.Axelrod, C.Chen, H.J.Chiu, T.Clayton, D.Das, M.C.Deller, L.Duan, D.Ernst, J.Feuerhelm, J.C.Grant, A.Grzechnik, L.Jaroszewski, K.K.Jin, H.A.Johnson, H.E.Klock, M.W.Knuth, P.Kozbial, S.S.Krishna, D.Marciano, D.McMullan, A.T.Morse, E.Nigoghossian, L.Okach, R.Reyes, C.L.Rife, N.Sefcovic, H.J.Tien, C.B.Trame, H.van den Bedem, D.Weekes, Q.Xu, K.O.Hodgson, J.Wooley, M.A.Elsliger, A.M.Deacon, A.Godzik, S.A.Lesley, and I.A.Wilson (2010).
Structures of the first representatives of Pfam family PF06938 (DUF1285) reveal a new fold with repeated structural motifs and possible involvement in signal transduction.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 66, 1218-1225.
PDB codes: 2ra9 2re3
20714670 R.Berrino, S.Cacchi, G.Fabrizi, A.Goggiamani, and P.Stabile (2010).
Arenediazonium tetrafluoroborates in palladium-catalyzed C-P bond-forming reactions. Synthesis of arylphosphonates, -phosphine oxides, and -phosphines.
  Org Biomol Chem, 8, 4518-4520.  
19288492 R.Maccari, R.Ottanà, R.Ciurleo, P.Paoli, G.Manao, G.Camici, C.Laggner, and T.Langer (2009).
Structure-based optimization of benzoic acids as inhibitors of protein tyrosine phosphatase 1B and low molecular weight protein tyrosine phosphatase.
  ChemMedChem, 4, 957-962.  
19622861 S.B.Patel, P.M.Cameron, S.J.O'Keefe, B.Frantz-Wattley, J.Thompson, E.A.O'Neill, T.Tennis, L.Liu, J.W.Becker, and G.Scapin (2009).
The three-dimensional structure of MAP kinase p38beta: different features of the ATP-binding site in p38beta compared with p38alpha.
  Acta Crystallogr D Biol Crystallogr, 65, 777-785.
PDB codes: 3gc7 3gc8 3gc9
17615669 K.Bharatham, N.Bharatham, and K.W.Lee (2007).
Pharmacophore modeling for protein tyrosine phosphatase 1B inhibitors.
  Arch Pharm Res, 30, 533-542.  
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.  
17543532 R.Maccari, P.Paoli, R.Ottanà, M.Jacomelli, R.Ciurleo, G.Manao, T.Steindl, T.Langer, M.G.Vigorita, and G.Camici (2007).
5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases.
  Bioorg Med Chem, 15, 5137-5149.  
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
16332678 J.Montalibet, K.Skorey, D.McKay, G.Scapin, E.Asante-Appiah, and B.P.Kennedy (2006).
Residues distant from the active site influence protein-tyrosine phosphatase 1B inhibitor binding.
  J Biol Chem, 281, 5258-5266.
PDB code: 2f6f
15013940 S.D.Taylor, and B.Hill (2004).
Recent advances in protein tyrosine phosphatase 1B inhibitors.
  Expert Opin Investig Drugs, 13, 199-214.  
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.