PDBsum entry 1pxh

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Hydrolase PDB id
Protein chain
297 a.a. *
ACY ×2
_MG ×2
Waters ×109
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of protein tyrosine phosphatase 1b with potent and selective bidentate inhibitor compound 2
Structure: Protein-tyrosine phosphatase, non-receptor type 1. Chain: a. Fragment: residues 1-321. Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ptp1b. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.15Å     R-factor:   0.200     R-free:   0.207
Authors: J.P.Sun,A.Fedorov,S.Y.Lee,X.L.Guo,K.Shen,D.S.Lawrence, S.C.Almo,Z.Y.Zhang
Key ref:
J.P.Sun et al. (2003). Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor. J Biol Chem, 278, 12406-12414. PubMed id: 12547827 DOI: 10.1074/jbc.M212491200
04-Jul-03     Release date:   12-Aug-03    
Supersedes: 1n6w
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

 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: 10.1074/jbc.M212491200 J Biol Chem 278:12406-12414 (2003)
PubMed id: 12547827  
Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor.
J.P.Sun, A.A.Fedorov, S.Y.Lee, X.L.Guo, K.Shen, D.S.Lawrence, S.C.Almo, Z.Y.Zhang.
Protein-tyrosine phosphatase 1B (PTP1B) has been implicated as an important regulator in several signaling pathways including those initiated by insulin and leptin. Potent and specific PTP1B inhibitors could serve as useful tools in elucidating the physiological functions of PTP1B and may constitute valuable therapeutics in the treatment of several human diseases. We have determined the crystal structure of PTP1B in complex with compound 2, the most potent and selective PTP1B inhibitor reported to date. The structure at 2.15-A resolution reveals that compound 2 simultaneously binds to the active site and a unique proximal noncatalytic site formed by Lys-41, Arg-47, and Asp-48. The structural data are further corroborated by results from kinetic analyses of the interactions of PTP1B and its site-directed mutants with compound 2 and several of its variants. Although many of the residues important for interactions between PTP1B and compound 2 are not unique to PTP1B, the combinations of all contact residues differ between PTP isozymes, which provide a structural basis for potent and selective PTP1B inhibition. Our data further suggest that potent, yet highly selective, PTP1B inhibitory agents can be acquired by targeting the area defined by residues Lys-41, Arg-47, and Asp-48, in addition to the previously identified second aryl phosphate-binding pocket.
  Selected figure(s)  
Figure 4.
Fig. 4. Interactions between 2 and PTP1B. a, H-bonding (blue dotted lines) and polar interactions (red dotted lines); b, hydrophobic interactions (orange dotted lines), and; c, interactions between the two fluorine atoms in F[2]Pmp and PTP1B. The cut-off distance used is 3.2 Å for hydrogen bonds, 4.0 Å for electrostatic or polar interactions, and 4.5 Å for hydrophobic interactions.
Figure 5.
Fig. 5. Interactions of Arg-47 and Lys-41 with the EGFR peptide (a), the PTP1B consensus peptide (b), compound 2 (c), and compound 4 (d). Hydrophobic interactions are indicated by orange dotted lines, H-bonds by blue dotted lines, and polar interactions by red dotted lines.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 12406-12414) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21371926 Y.S.Choong, T.S.Lim, A.L.Chew, I.Aziah, and A.Ismail (2011).
Structural and functional studies of a 50 kDa antigenic protein from Salmonella enterica serovar Typhi.
  J Mol Graph Model, 29, 834-842.  
20644889 K.A.Rawls, C.Grundner, and J.A.Ellman (2010).
Design and synthesis of nonpeptidic, small molecule inhibitors for the Mycobacterium tuberculosis protein tyrosine phosphatase PtpB.
  Org Biomol Chem, 8, 4066-4070.  
20520657 R.Huang, I.Martinez-Ferrando, and P.A.Cole (2010).
Enhanced interrogation: emerging strategies for cell signaling inhibition.
  Nat Struct Mol Biol, 17, 646-649.  
  20957214 T.Scior, J.A.Guevara-García, F.J.Melendez, H.H.Abdallah, Q.T.Do, and P.Bernard (2010).
Chimeric design, synthesis, and biological assays of a new nonpeptide insulin-mimetic vanadium compound to inhibit protein tyrosine phosphatase 1B.
  Drug Des Devel Ther, 4, 231-242.  
20170098 X.Zhang, Y.He, S.Liu, Z.Yu, Z.X.Jiang, Z.Yang, Y.Dong, S.C.Nabinger, L.Wu, A.M.Gunawan, L.Wang, R.J.Chan, and Z.Y.Zhang (2010).
Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2).
  J Med Chem, 53, 2482-2493.
PDB codes: 3jrl 3o5x
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.  
  19920909 T.Scior, H.G.Mack, J.A.García, and W.Koch (2009).
Antidiabetic Bis-Maltolato-OxoVanadium(IV): Conversion of inactive trans- to bioactive cis-BMOV for possible binding to target PTP-1B.
  Drug Des Devel Ther, 2, 221-231.  
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.  
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.  
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
18259840 Z.X.Jiang, and Z.Y.Zhang (2008).
Targeting PTPs with small molecule inhibitors in cancer treatment.
  Cancer Metastasis Rev, 27, 263-272.  
17567745 A.A.Puhl, R.J.Gruninger, R.Greiner, T.W.Janzen, S.C.Mosimann, and L.B.Selinger (2007).
Kinetic and structural analysis of a bacterial protein tyrosine phosphatase-like myo-inositol polyphosphatase.
  Protein Sci, 16, 1368-1378.
PDB codes: 2b4o 2b4p 2b4u
17038557 C.D.Morrison, C.L.White, Z.Wang, S.Y.Lee, D.S.Lawrence, W.T.Cefalu, Z.Y.Zhang, and T.W.Gettys (2007).
Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age.
  Endocrinology, 148, 433-440.  
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.  
18058037 S.C.Almo, J.B.Bonanno, J.M.Sauder, S.Emtage, T.P.Dilorenzo, V.Malashkevich, S.R.Wasserman, S.Swaminathan, S.Eswaramoorthy, R.Agarwal, D.Kumaran, M.Madegowda, S.Ragumani, Y.Patskovsky, J.Alvarado, U.A.Ramagopal, J.Faber-Barata, M.R.Chance, A.Sali, A.Fiser, Z.Y.Zhang, D.S.Lawrence, and S.K.Burley (2007).
Structural genomics of protein phosphatases.
  J Struct Funct Genomics, 8, 121-140.
PDB codes: 1rxd 2fh7 2g59 2hcm 2hhl 2hxp 2hy3 2i0o 2i1y 2i44 2iq1 2irm 2isn 2nv5 2oyc 2p27 2p4u 2p69 2p8e 2pbn 2q5e 2qjc 2r0b
18056643 X.Yu, J.P.Sun, Y.He, X.Guo, S.Liu, B.Zhou, A.Hudmon, and Z.Y.Zhang (2007).
Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases.
  Proc Natl Acad Sci U S A, 104, 19767-19772.  
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.  
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
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.