PDBsum entry 1no6

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Hydrolase PDB id
Jmol PyMol
Protein chain
283 a.a. *
Waters ×258
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Potent, selective protein tyrosine phosphatase 1b inhibitor compound 5 using a linked-fragment strategy
Structure: Protein-tyrosine phosphatase, non-receptor type 1. Chain: a. Fragment: ptp1b 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.
2.40Å     R-factor:   0.204     R-free:   0.267
Authors: B.G.Szczepankiewicz,G.Liu,P.J.Hajduk,C.Abad-Zapatero,Z.Pei, Z.Xin,T.Lubben,J.M.Trevillyan,M.A.Stashko,S.J.Ballaron, H.Liang,F.Huang,C.W.Hutchins,S.W.Fesik,M.R.Jirousek
Key ref: B.G.Szczepankiewicz et al. (2003). Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy. J Am Chem Soc, 125, 4087-4096. PubMed id: 12670229 DOI: 10.1021/ja0296733
15-Jan-03     Release date:   08-Apr-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
435 a.a.
283 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
Bound ligand (Het Group name = 794)
matches with 40.00% similarity
+ phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein dephosphorylation   1 term 
  Biochemical function     protein tyrosine phosphatase activity     1 term  


DOI no: 10.1021/ja0296733 J Am Chem Soc 125:4087-4096 (2003)
PubMed id: 12670229  
Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy.
B.G.Szczepankiewicz, G.Liu, P.J.Hajduk, C.Abad-Zapatero, Z.Pei, Z.Xin, T.H.Lubben, J.M.Trevillyan, M.A.Stashko, S.J.Ballaron, H.Liang, F.Huang, C.W.Hutchins, S.W.Fesik, M.R.Jirousek.
Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
20205445 R.G.Coleman, and K.A.Sharp (2010).
Protein pockets: inventory, shape, and comparison.
  J Chem Inf Model, 50, 589-603.  
  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.  
19618939 D.R.Davies, B.Mamat, O.T.Magnusson, J.Christensen, M.H.Haraldsson, R.Mishra, B.Pease, E.Hansen, J.Singh, D.Zembower, H.Kim, A.S.Kiselyov, A.B.Burgin, M.E.Gurney, and L.J.Stewart (2009).
Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.
  J Med Chem, 52, 4694-4715.
PDB codes: 3fts 3ftu 3ftv 3ftw 3ftx 3fty 3fu0 3fu3 3fu5 3fu6 3fud 3fue 3fuf 3fuh 3fui 3fuj 3fuk 3fum 3fun
19443265 Kloe, D.Bailey, R.Leurs, and Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
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.  
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.  
19172689 M.Pellecchia, I.Bertini, D.Cowburn, C.Dalvit, E.Giralt, W.Jahnke, T.L.James, S.W.Homans, H.Kessler, C.Luchinat, B.Meyer, H.Oschkinat, J.Peng, H.Schwalbe, and G.Siegal (2008).
Perspectives on NMR in drug discovery: a technique comes of age.
  Nat Rev Drug Discov, 7, 738-745.  
18292873 S.L.Ng, P.Y.Yang, K.Y.Chen, R.Srinivasan, and S.Q.Yao (2008).
"Click" synthesis of small-molecule inhibitors targeting caspases.
  Org Biomol Chem, 6, 844-847.  
17541991 C.H.Röhrig, C.Loch, J.Y.Guan, G.Siegal, and M.Overhand (2007).
Fragment-Based Synthesis and SAR of Modified FKBP Ligands: Influence of Different Linking on Binding Affinity.
  ChemMedChem, 2, 1054-1070.  
17377675 G.Gasparini, M.Martin, L.J.Prins, and P.Scrimin (2007).
Limitations of the "tethering" strategy for the detection of a weak noncovalent interaction.
  Chem Commun (Camb), (), 1340-1342.  
17657909 J.Klages, M.Coles, and H.Kessler (2007).
NMR-based screening: a powerful tool in fragment-based drug discovery.
  Analyst, 132, 693-705.  
17394300 J.Vazquez, L.Tautz, J.J.Ryan, K.Vuori, T.Mustelin, and M.Pellecchia (2007).
Development of molecular probes for second-site screening and design of protein tyrosine phosphatase inhibitors.
  J Med Chem, 50, 2137-2143.  
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.  
17290284 P.J.Hajduk, and J.Greer (2007).
A decade of fragment-based drug design: strategic advances and lessons learned.
  Nat Rev Drug Discov, 6, 211-219.  
18007601 R.Srinivasan, J.Li, S.L.Ng, K.A.Kalesh, and S.Q.Yao (2007).
Methods of using click chemistry in the discovery of enzyme inhibitors.
  Nat Protoc, 2, 2655-2664.  
16919785 A.J.Barr, and S.Knapp (2006).
MAPK-specific tyrosine phosphatases: new targets for drug discovery?
  Trends Pharmacol Sci, 27, 525-530.  
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
16769216 E.W.Yue, B.Wayland, B.Douty, M.L.Crawley, E.McLaughlin, A.Takvorian, Z.Wasserman, M.J.Bower, M.Wei, Y.Li, P.J.Ala, L.Gonneville, R.Wynn, T.C.Burn, P.C.Liu, and A.P.Combs (2006).
Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: synthesis and structure-activity relationships of a peptide scaffold.
  Bioorg Med Chem, 14, 5833-5849.  
16846802 G.M.Keseru, and G.M.Makara (2006).
Hit discovery and hit-to-lead approaches.
  Drug Discov Today, 11, 741-748.  
16916797 P.J.Ala, L.Gonneville, M.C.Hillman, M.Becker-Pasha, M.Wei, B.G.Reid, R.Klabe, E.W.Yue, B.Wayland, B.Douty, P.Polam, Z.Wasserman, M.Bower, A.P.Combs, T.C.Burn, G.F.Hollis, and R.Wynn (2006).
Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.
  J Biol Chem, 281, 32784-32795.
PDB codes: 2cm2 2cm3 2cm7 2cm8 2cma 2cmb 2cmc
17028182 P.J.Ala, L.Gonneville, M.Hillman, M.Becker-Pasha, E.W.Yue, B.Douty, B.Wayland, P.Polam, M.L.Crawley, E.McLaughlin, R.B.Sparks, B.Glass, A.Takvorian, A.P.Combs, T.C.Burn, G.F.Hollis, and R.Wynn (2006).
Structural insights into the design of nonpeptidic isothiazolidinone-containing inhibitors of protein-tyrosine phosphatase 1B.
  J Biol Chem, 281, 38013-38021.
PDB codes: 2cne 2cnf 2cng 2cnh 2cni
16388629 X.Mei, A.T.August, and C.Wolf (2006).
Regioselective copper-catalyzed amination of chlorobenzoic acids: synthesis and solid-state structures of N-aryl anthranilic acid derivatives.
  J Org Chem, 71, 142-149.  
15389851 K.F.Geoghegan, and M.A.Kelly (2005).
Biochemical applications of mass spectrometry in pharmaceutical drug discovery.
  Mass Spectrom Rev, 24, 347-366.  
15900534 L.Bialy, and H.Waldmann (2005).
Inhibitors of protein tyrosine phosphatases: next-generation drugs?
  Angew Chem Int Ed Engl, 44, 3814-3839.  
15608376 R.A.Judge, K.Swift, and C.González (2005).
An ultraviolet fluorescence-based method for identifying and distinguishing protein crystals.
  Acta Crystallogr D Biol Crystallogr, 61, 60-66.  
16006182 S.P.Williams, L.F.Kuyper, and K.H.Pearce (2005).
Recent applications of protein crystallography and structure-guided drug design.
  Curr Opin Chem Biol, 9, 371-380.  
15326593 A.M.Aronov, and G.W.Bemis (2004).
A minimalist approach to fragment-based ligand design using common rings and linkers: application to kinase inhibitors.
  Proteins, 57, 36-50.  
15286733 D.C.Rees, M.Congreve, C.W.Murray, and R.Carr (2004).
Fragment-based lead discovery.
  Nat Rev Drug Discov, 3, 660-672.  
15024017 I.K.Lund, H.S.Andersen, L.F.Iversen, O.H.Olsen, K.B.Møller, A.K.Pedersen, Y.Ge, D.D.Holsworth, M.J.Newman, F.U.Axe, and N.P.Møller (2004).
Structure-based design of selective and potent inhibitors of protein-tyrosine phosphatase beta.
  J Biol Chem, 279, 24226-24235.  
15013940 S.D.Taylor, and B.Hill (2004).
Recent advances in protein tyrosine phosphatase 1B inhibitors.
  Expert Opin Investig Drugs, 13, 199-214.  
12946643 M.Coles, M.Heller, and H.Kessler (2003).
NMR-based screening technologies.
  Drug Discov Today, 8, 803-810.  
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.