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Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.
Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2006 Oct 27; Vol. 281 (43), pp. 32784-95. Date of Electronic Publication: 2006 Aug 17. - Publication Year :
- 2006
-
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.
- Subjects :
- Binding Sites
Catalytic Domain
Crystallography, X-Ray
Escherichia coli genetics
Humans
Hydrogen Bonding
Hydrolysis
Inhibitory Concentration 50
Kinetics
Models, Molecular
Molecular Structure
Protein Conformation drug effects
Protein Structure, Secondary
Protein Structure, Tertiary
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatases analysis
Protein Tyrosine Phosphatases isolation & purification
Structure-Activity Relationship
Substrate Specificity
Water chemistry
Molecular Mimicry
Organophosphonates pharmacology
Protein Tyrosine Phosphatases antagonists & inhibitors
Protein Tyrosine Phosphatases chemistry
Thiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 281
- Issue :
- 43
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16916797
- Full Text :
- https://doi.org/10.1074/jbc.M606873200