PDBsum entry 2cni

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Hydrolase PDB id
Jmol PyMol
Protein chain
300 a.a. *
Waters ×302
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Structural insights into the design of nonpeptidic isothiazolidinone-containing inhibitors of protein tyrosine phosphatase 1b
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.
2.00Å     R-factor:   0.203     R-free:   0.247
Authors: 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,R.Wynn
Key ref:
P.J.Ala et al. (2006). Structural insights into the design of nonpeptidic isothiazolidinone-containing inhibitors of protein-tyrosine phosphatase 1B. J Biol Chem, 281, 38013-38021. PubMed id: 17028182 DOI: 10.1074/jbc.M607913200
21-May-06     Release date:   27-Sep-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
435 a.a.
300 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     protein dephosphorylation   1 term 
  Biochemical function     protein tyrosine phosphatase activity     1 term  


DOI no: 10.1074/jbc.M607913200 J Biol Chem 281:38013-38021 (2006)
PubMed id: 17028182  
Structural insights into the design of nonpeptidic isothiazolidinone-containing inhibitors of protein-tyrosine phosphatase 1B.
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, R.Wynn.
Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp(48), and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water molecule. Although both substituents retain the favorable hydrogen bonding network of the peptide scaffold, their aryl rings interact weakly with the protein. The aryl ring of benzimidazole is partially solvent exposed and only participates in van der Waals interactions with Phe(182) of the flap. The aryl ring of aryl sulfonamide adopts an unexpected conformation and only participates in intramolecular pi-stacking interactions with the benzimidazole ring. These results explain the flat SAR for substitutions on both rings and the reason why unsubstituted moieties were selected as candidates. Finally, substituents ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the primary phosphate binding pocket. The crystal structure of an o-chloro derivative reveals that chlorine interacts extensively with residues in the small site. The structural insights that have led to the discovery of potent benzimidazole aryl sulfonamide o-substituted derivatives are discussed in detail.
  Selected figure(s)  
Figure 3.
FIGURE 3. Crystal structure of PTP1B/1. The proximal DFMP moiety of 1 (ball-and-stick) binds at the center of the phosphate binding loop (thick bonds); the C-terminal amide and adjacent amide NHs hydrogen bond (dashed lines) to the carboxylate of Asp^48 at the A-C border; the distal amide CO hydrogen bonds to the backbone NH of Arg^47; and the distal DFMP interacts with Lys^41 and Arg^47 in the C site. Estimated contributions to the overall ligand binding affinity for each substituent are also indicated.
Figure 5.
FIGURE 5. Crystal structure of PTP1B/5. The ortho-Cl substituent of the inhibitor binds in the D site where it participates in VDW interactions with Tyr^46, Ser^216, Asp^181, and Phe^182 and it is only 3.1 and 3.5 Å from one of the sulfone oxygens and the CH of the heterocycle, respectively. The IZD-phenyl template and aryl sulfonamide bind in previously observed conformations, and salicylate binds in the B site where it is in VDW contact with Met^258 and hydrogen bonds to Arg^24 and Arg^254. The linker that spans the A and B sites is well defined in the electron density even though it does not interact extensively with nonpolar residues.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 38013-38021) 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.  
20617368 L.Lu, S.Wang, M.Zhu, Z.Liu, M.Guo, S.Xing, and X.Fu (2010).
Inhibition protein tyrosine phosphatases by an oxovanadium glutamate complex, Na2[VO(Glu)2(CH3OH)](Glu = glutamate).
  Biometals, 23, 1139-1147.  
19553129 D.Minond, S.A.Saldanha, P.Subramaniam, M.Spaargaren, T.Spicer, J.R.Fotsing, T.Weide, V.V.Fokin, K.B.Sharpless, M.Galleni, C.Bebrone, P.Lassaux, and P.Hodder (2009).
Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries.
  Bioorg Med Chem, 17, 5027-5037.  
17331067 M.M.Sale, and S.S.Rich (2007).
Genetic contributions to type 2 diabetes: recent insights.
  Expert Rev Mol Diagn, 7, 207-217.  
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.