PDBsum entry 1t49

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Hydrolase PDB id
Protein chain
282 a.a. *
Waters ×235
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Allosteric inhibition of protein tyrosine phosphatase 1b
Structure: Protein-tyrosine phosphatase, non-receptor type 1. Chain: a. Fragment: residues 1-298. Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn1, ptp1b. Expressed in: escherichia coli. Expression_system_taxid: 562
1.90Å     R-factor:   0.207     R-free:   0.236
Authors: C.Wiesmann,K.J.Barr,J.Kung,J.Zhu,W.Shen,B.J.Fahr,M.Zhong, L.Taylor,M.Randal,R.S.Mcdowell,S.K.Hansen
Key ref:
C.Wiesmann et al. (2004). Allosteric inhibition of protein tyrosine phosphatase 1B. Nat Struct Mol Biol, 11, 730-737. PubMed id: 15258570 DOI: 10.1038/nsmb803
28-Apr-04     Release date:   20-Jul-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
435 a.a.
282 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: 10.1038/nsmb803 Nat Struct Mol Biol 11:730-737 (2004)
PubMed id: 15258570  
Allosteric inhibition of protein tyrosine phosphatase 1B.
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, S.K.Hansen.
Obesity and type II diabetes are closely linked metabolic syndromes that afflict >100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located approximately 20 A from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases.
  Selected figure(s)  
Figure 2.
Figure 2. Crystal structures reveal a novel allosteric site in PTP1B. (a) Inhibitor 2 (spheres) binds in a groove formed by helices 3 and 6 that positions the catalytically important WPD loop. Distance from the active site Cys is 20 ┼. (b) Compound 2 binds in a hydrophobic pocket formed by Leu192, Phe196 and Phe280. Hydrogen bonds with side chains of Glu276, Asn193 and the main chain carbonyl of Phe196 (water-mediated) are shown. (c) Overlay of the crystal structures of compounds 1 (orange, 2.2-┼ resolution), 2 (yellow, 1.9-┼ resolution) and 3 (blue sticks and mesh, 2.7 ┼ resolution). The benzofuran core of the three compounds occupies the same hydrophobic site. Allosteric inhibitors progressively wrap around Phe280, correlating with increasing potency. PTP1B and the side chain of Phe280 are gray. This figure was created using PyMOL (DeLano Scientific;
Figure 7.
Figure 7. The allosteric-bound conformation is similar to conformations of PTP1B with the WPD loop in the open conformation. (a) Overlay of 16 structures of PTP1B with the WPD loop in the open conformation (black), along with PTP1B bound to compound 2 (spheres, protein in magenta), and the closed conformation (green, PDB entry 1PTY). Alignment shows that the allosteric-bound conformation is similar to many open conformations. (b) Allosteric inhibitor binds to the naturally occurring open conformation (E[o]) of PTP1B and inhibits activity by blocking closure of the WPD loop. Compound cannot bind to the closed conformation.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2004, 11, 730-737) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21123182 E.Ferrari, M.Tinti, S.Costa, S.Corallino, A.P.Nardozza, A.Chatraryamontri, A.Ceol, G.Cesareni, and L.Castagnoli (2011).
Identification of new substrates of the protein-tyrosine phosphatase PTP1B by Bayesian integration of proteome evidence.
  J Biol Chem, 286, 4173-4185.  
21420867 V.V.Vintonyak, H.Waldmann, and D.Rauh (2011).
Using small molecules to target protein phosphatases.
  Bioorg Med Chem, 19, 2145-2155.  
20084112 C.Valmas, M.N.Grosch, M.Schümann, J.Olejnik, O.Martinez, S.M.Best, V.Krähling, C.F.Basler, and E.Mühlberger (2010).
Marburg virus evades interferon responses by a mechanism distinct from ebola virus.
  PLoS Pathog, 6, e1000721.  
20080972 K.C.Carver, T.M.Piazza, and L.A.Schuler (2010).
Prolactin enhances insulin-like growth factor I receptor phosphorylation by decreasing its association with the tyrosine phosphatase SHP-2 in MCF-7 breast cancer cells.
  J Biol Chem, 285, 8003-8012.  
20041871 L.Sylvest, C.D.Bendiksen, and G.Houen (2010).
Phosphatase inhibitors with anti-angiogenic effect in vitro.
  APMIS, 118, 49-59.  
20564495 M.Na, P.T.Thuong, I.H.Hwang, K.Bae, B.Y.Kim, H.Osada, and J.S.Ahn (2010).
Protein tyrosine phosphatase 1B inhibitory activity of 24-norursane triterpenes isolated from Weigela subsessilis.
  Phytother Res, 24, 1716-1719.  
20221654 R.A.Ward (2010).
Using protein-ligand docking to assess the chemical tractability of inhibiting a protein target.
  J Mol Model, 16, 1833-1843.  
20444318 V.S.Muthusamy, C.Saravanababu, M.Ramanathan, R.Bharathi Raja, S.Sudhagar, S.Anand, and B.S.Lakshmi (2010).
Inhibition of protein tyrosine phosphatase 1B and regulation of insulin signalling markers by caffeoyl derivatives of chicory ( Cichorium intybus) salad leaves.
  Br J Nutr, 104, 813-823.  
19810703 D.Vidovi─ç, 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.  
19229311 M.D.Daily, and J.J.Gray (2009).
Allosteric communication occurs via networks of tertiary and quaternary motions in proteins.
  PLoS Comput Biol, 5, e1000293.  
19240079 N.J.Beresford, D.Mulhearn, B.Szczepankiewicz, G.Liu, M.E.Johnson, A.Fordham-Skelton, C.Abad-Zapatero, J.S.Cavet, and L.Tabernero (2009).
Inhibition of MptpB phosphatase from Mycobacterium tuberculosis impairs mycobacterial survival in macrophages.
  J Antimicrob Chemother, 63, 928-936.  
19604469 T.D.Bugg (2009).
Oxygenases get to grips with polypeptides.
  Structure, 17, 913-914.  
19410499 V.V.Vintonyak, A.P.Antonchick, D.Rauh, and H.Waldmann (2009).
The therapeutic potential of phosphatase inhibitors.
  Curr Opin Chem Biol, 13, 272-283.  
19262557 Y.Zhang, Y.Li, Y.W.Guo, H.L.Jiang, and X.Shen (2009).
A sesquiterpene quinone, dysidine, from the sponge Dysidea villosa, activates the insulin pathway through inhibition of PTPases.
  Acta Pharmacol Sin, 30, 333-345.  
18855677 A.Bakan, J.S.Lazo, P.Wipf, K.M.Brummond, and I.Bahar (2008).
Toward a molecular understanding of the interaction of dual specificity phosphatases with substrates: insights from structure-based modeling and high throughput screening.
  Curr Med Chem, 15, 2536-2544.  
18480265 J.C.Juarez, M.Manuia, M.E.Burnett, O.Betancourt, B.Boivin, D.E.Shaw, N.K.Tonks, A.P.Mazar, and F.Doñate (2008).
Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling.
  Proc Natl Acad Sci U S A, 105, 7147-7152.  
18685809 K.Bharatham, N.Bharatham, Y.J.Kwon, and K.W.Lee (2008).
Molecular dynamics simulation study of PTP1B with allosteric inhibitor and its application in receptor based pharmacophore modeling.
  J Comput Aided Mol Des, 22, 925-933.  
18298793 L.Tabernero, A.R.Aricescu, E.Y.Jones, and S.E.Szedlacsek (2008).
Protein tyrosine phosphatases: structure-function relationships.
  FEBS J, 275, 867-882.  
19012396 S.Liu, L.F.Zeng, L.Wu, X.Yu, T.Xue, A.M.Gunawan, Y.Q.Long, and Z.Y.Zhang (2008).
Targeting inactive enzyme conformation: aryl diketoacid derivatives as a new class of PTP1B inhibitors.
  J Am Chem Soc, 130, 17075-17084.
PDB codes: 3eax 3eb1
17531094 A.Del Sol, M.J.Araúzo-Bravo, D.Amoros, and R.Nussinov (2007).
Modular architecture of protein structures and allosteric communications: potential implications for signaling proteins and regulatory linkages.
  Genome Biol, 8, R92.  
17997129 K.Fenn, and K.R.Matthews (2007).
The cell biology of Trypanosoma brucei differentiation.
  Curr Opin Microbiol, 10, 539-546.  
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.  
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.  
17546659 T.S.Girish, and B.Gopal (2007).
The crystal structure of the catalytic domain of the chick retinal neurite inhibitor-receptor protein tyrosine phosphatase CRYP-2/cPTPRO.
  Proteins, 68, 1011-1015.
PDB code: 2pi7
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.  
17346049 X.Y.Zhang, and A.C.Bishop (2007).
Site-specific incorporation of allosteric-inhibition sites in a protein tyrosine phosphatase.
  J Am Chem Soc, 129, 3812-3813.  
16919785 A.J.Barr, and S.Knapp (2006).
MAPK-specific tyrosine phosphatases: new targets for drug discovery?
  Trends Pharmacol Sci, 27, 525-530.  
17043136 B.Szöor, J.Wilson, H.McElhinney, L.Tabernero, and K.R.Matthews (2006).
Protein tyrosine phosphatase TbPTP1: A molecular switch controlling life cycle differentiation in trypanosomes.
  J Cell Biol, 175, 293-303.  
16582877 D.F.Lazar, and A.R.Saltiel (2006).
Lipid phosphatases as drug discovery targets for type 2 diabetes.
  Nat Rev Drug Discov, 5, 333-342.  
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
16618703 J.S.Swaney, H.H.Patel, U.Yokoyama, B.P.Head, D.M.Roth, and P.A.Insel (2006).
Focal adhesions in (myo)fibroblasts scaffold adenylyl cyclase with phosphorylated caveolin.
  J Biol Chem, 281, 17173-17179.  
16752372 S.Yang, M.K.Na, J.P.Jang, K.A.Kim, B.Y.Kim, N.J.Sung, W.K.Oh, and J.S.Ahn (2006).
Inhibition of protein tyrosine phosphatase 1B by lignans from Myristica fragrans.
  Phytother Res, 20, 680-682.  
16698773 X.Hu, and C.E.Stebbins (2006).
Dynamics of the WPD loop of the Yersinia protein tyrosine phosphatase.
  Biophys J, 91, 948-956.  
16002394 C.Steegborn, T.N.Litvin, K.C.Hess, A.B.Capper, R.Taussig, J.Buck, L.R.Levin, and H.Wu (2005).
A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen.
  J Biol Chem, 280, 31754-31759.
PDB code: 2bw7
15550394 E.Buck, H.Bourne, and J.A.Wells (2005).
Site-specific disulfide capture of agonist and antagonist peptides on the C5a receptor.
  J Biol Chem, 280, 4009-4012.  
16271887 S.Li, R.S.Depetris, D.Barford, J.Chernoff, and S.R.Hubbard (2005).
Crystal structure of a complex between protein tyrosine phosphatase 1B and the insulin receptor tyrosine kinase.
  Structure, 13, 1643-1651.
PDB code: 2b4s
15314233 J.A.Hardy, J.Lam, J.T.Nguyen, T.O'Brien, and J.A.Wells (2004).
Discovery of an allosteric site in the caspases.
  Proc Natl Acad Sci U S A, 101, 12461-12466.
PDB codes: 1shj 1shl
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