spacer
spacer

PDBsum entry 1q1m

Go to PDB code: 
protein ligands links
Hydrolase PDB id
1q1m
Jmol
Contents
Protein chain
299 a.a. *
Ligands
234
Waters ×124
* Residue conservation analysis
PDB id:
1q1m
Name: Hydrolase
Title: A highly efficient approach to a selective and cell active ptp1b inhibitors
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. Expression_system_taxid: 562.
Resolution:
2.60Å     R-factor:   0.208     R-free:   0.223
Authors: G.Liu,Z.Xin,Z.Pei,P.J.Hajduk,C.Abad-Zapatero,C.W.Hutchins, H.Zhao,T.H.Lubben,S.J.Ballaron,D.L.Haasch,W.Kaszubska, C.M.Rondinone,J.M.Trevillyan,M.R.Jirousek
Key ref: G.Liu et al. (2003). Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor. J Med Chem, 46, 4232-4235. PubMed id: 13678400 DOI: 10.1021/jm034122o
Date:
22-Jul-03     Release date:   16-Sep-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
Seq:
Struc:
435 a.a.
299 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/jm034122o J Med Chem 46:4232-4235 (2003)
PubMed id: 13678400  
 
 
Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor.
G.Liu, Z.Xin, Z.Pei, P.J.Hajduk, C.Abad-Zapatero, C.W.Hutchins, H.Zhao, T.H.Lubben, S.J.Ballaron, D.L.Haasch, W.Kaszubska, C.M.Rondinone, J.M.Trevillyan, M.R.Jirousek.
 
  ABSTRACT  
 
Using an NMR-based fragment screening and X-ray crystal structure-based assembly, starting with millimolar ligands for both the catalytic site and the second phosphotyrosine binding site, we have identified a small-molecule inhibitor of protein tyrosine phosphatase 1B with low micromolar inhibition constant, high selectivity (30-fold) over the highly homologous T-cell protein tyrosine phosphatase, and good cellular activity in COS-7 cells.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20223699 A.G.Coyne, D.E.Scott, and C.Abell (2010).
Drugging challenging targets using fragment-based approaches.
  Curr Opin Chem Biol, 14, 299-307.  
20386843 J.Ge, H.Wu, and S.Q.Yao (2010).
An unnatural amino acid that mimics phosphotyrosine.
  Chem Commun (Camb), 46, 2980-2982.  
20404926 N.Huang, and M.P.Jacobson (2010).
Binding-site assessment by virtual fragment screening.
  PLoS One, 5, e10109.  
20205445 R.G.Coleman, and K.A.Sharp (2010).
Protein pockets: inventory, shape, and comparison.
  J Chem Inf Model, 50, 589-603.  
19810703 D.Vidović, 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.  
19443265 G.E.de Kloe, D.Bailey, R.Leurs, and I.J.de Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
18855890 M.L.Mohler, Y.He, Z.Wu, D.J.Hwang, and D.D.Miller (2009).
Recent and emerging anti-diabetes targets.
  Med Res Rev, 29, 125-195.  
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.  
19590777 R.Srinivasan, L.P.Tan, H.Wu, P.Y.Yang, K.A.Kalesh, and S.Q.Yao (2009).
High-throughput synthesis of azide libraries suitable for direct "click" chemistry and in situ screening.
  Org Biomol Chem, 7, 1821-1828.  
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.  
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.  
17516842 N.C.Bal, H.Agrawal, A.K.Meher, and A.Arora (2007).
Characterization of peptidyl-tRNA hydrolase encoded by open reading frame Rv1014c of Mycobacterium tuberculosis H37Rv.
  Biol Chem, 388, 467-479.  
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.  
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.  
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
17039461 S.Lee, and Q.Wang (2007).
Recent development of small molecular specific inhibitor of protein tyrosine phosphatase 1B.
  Med Res Rev, 27, 553-573.  
16919785 A.J.Barr, and S.Knapp (2006).
MAPK-specific tyrosine phosphatases: new targets for drug discovery?
  Trends Pharmacol Sci, 27, 525-530.  
16580603 A.J.Orry, R.A.Abagyan, and C.N.Cavasotto (2006).
Structure-based development of target-specific compound libraries.
  Drug Discov Today, 11, 261-266.  
16557282 A.Ostman, C.Hellberg, and F.D.Böhmer (2006).
Protein-tyrosine phosphatases and cancer.
  Nat Rev Cancer, 6, 307-320.  
15925537 E.R.Zartler, and M.J.Shapiro (2005).
Fragonomics: fragment-based drug discovery.
  Curr Opin Chem Biol, 9, 366-370.  
15900534 L.Bialy, and H.Waldmann (2005).
Inhibitors of protein tyrosine phosphatases: next-generation drugs?
  Angew Chem Int Ed Engl, 44, 3814-3839.  
15286733 D.C.Rees, M.Congreve, C.W.Murray, and R.Carr (2004).
Fragment-based lead discovery.
  Nat Rev Drug Discov, 3, 660-672.  
15288248 H.O.Villar, J.Yan, and M.R.Hansen (2004).
Using NMR for ligand discovery and optimization.
  Curr Opin Chem Biol, 8, 387-391.  
15013940 S.D.Taylor, and B.Hill (2004).
Recent advances in protein tyrosine phosphatase 1B inhibitors.
  Expert Opin Investig Drugs, 13, 199-214.  
14662006 G.Liu (2003).
Metabolic Diseases Drug Discovery World Summit.
  Expert Opin Emerg Drugs, 8, 577-582.  
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.