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PDBsum entry 2cma

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Hydrolase PDB id
2cma
Jmol
Contents
Protein chain
297 a.a. *
Ligands
F20
Waters ×192
* Residue conservation analysis
PDB id:
2cma
Name: Hydrolase
Title: Structural basis for inhibition of protein tyrosine phosphatase 1b by isothiazolidinone heterocyclic phosphonate mimetics
Structure: Tyrosine-protein phosphatase non-receptor type 1. Chain: a. Fragment: catalytic domain, residues 1-321. Synonym: protein tyrosine phosphatase 1b, ptp-1b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.30Å     R-factor:   0.203     R-free:   0.278
Authors: 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,A.P.Combs, P.Polam,Z.Wasserman,M.Bower,T.C.Burn,G.F.Hollis,R.Wynn
Key ref:
P.J.Ala et al. (2006). Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics. J Biol Chem, 281, 32784-32795. PubMed id: 16916797 DOI: 10.1074/jbc.M606873200
Date:
04-May-06     Release date:   17-Aug-06    
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.
297 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: 10.1074/jbc.M606873200 J Biol Chem 281:32784-32795 (2006)
PubMed id: 16916797  
 
 
Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.
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, R.Wynn.
 
  ABSTRACT  
 
Crystal structures of protein-tyrosine phosphatase 1B in complex with compounds bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal that the heterocycle is highly complementary to the catalytic pocket of the protein. The heterocycle participates in an extensive network of hydrogen bonds with the backbone of the phosphate-binding loop, Phe(182) of the flap, and the side chain of Arg(221). When substituted with a phenol, the small inhibitor induces the closed conformation of the protein and displaces all waters in the catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors than unsaturated analogs because the IZD heterocycle and phenyl ring directly attached to it bind in a nearly orthogonal orientation with respect to each other, a conformation that is close to the energy minimum of the saturated IZD-phenyl moiety. These results explain why the heterocycle is a potent phosphonate mimetic and an ideal starting point for designing small nonpeptidic inhibitors.
 
  Selected figure(s)  
 
Figure 2.
FIGURE 2. Crystal structure of PTP1B/1. a, superposition of the bound conformations of the phosphonate mimetics of compounds 1, 5, and 1G7G. Note the IZD heterocycle of 1 mimics the interactions of DFMP and CMBA, and it displaces four waters. b, stereo view of the 2F[o] - F[c] simulated annealed omit map (contoured at 1 ) and atomic model for PTP1B/1. The inhibitor was omitted from the model prior to a cycle of simulated annealing and was not used in the calculation of phases. c, stereo view of 1 (ball-and-stick) bound in the A site. Dashed lines indicate 10 potential hydrogen bonds between the inhibitor and residues in the active site.
Figure 6.
FIGURE 6. Bound conformations of saturated and unsaturated IZD-phenyl moieties. a, the relative angle between the unsaturated IZD and phenyl rings of 1 is 70-75°. b, superposition of the unsaturated IZD 1 (stick bonds) and the saturated (S)-IZD-phenyl moiety of 2 (ball-and-stick). Note the phenyl ring and heteroatoms of IZD bind in the same position whether or not the heterocycle is reduced.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 32784-32795) copyright 2006.  
  Figures were selected by the author.  

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.  
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.  
20236928 T.A.Brandão, A.C.Hengge, and S.J.Johnson (2010).
Insights into the reaction of protein-tyrosine phosphatase 1B: crystal structures for transition state analogs of both catalytic steps.
  J Biol Chem, 285, 15874-15883.
PDB codes: 3i7z 3i80
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.  
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