Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics
| Autor: | Milton Hillman, Andrew P. Combs, Paul J. Ala, Ronald M. Klabe, Brian Wayland, Brent Douty, Michael J. Bower, Min Wei, Eddy W. Yue, Brian Reid, Mary Becker-Pasha, Gregory Hollis, Timothy Burn, Lucie Gonneville, Padmaja Polam, Richard Wynn, Zelda Wasserman |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Stereochemistry Protein Conformation Phosphatase Organophosphonates Ring (chemistry) Crystallography X-Ray Biochemistry Protein Structure Secondary Catalysis Substrate Specificity chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship Catalytic Domain Hydrolase Side chain Escherichia coli Moiety Humans Molecular Biology Protein Tyrosine Phosphatase Non-Receptor Type 1 Binding Sites Molecular Structure Hydrogen bond Hydrolysis Molecular Mimicry Water Hydrogen Bonding Cell Biology Phosphonate Protein Structure Tertiary Kinetics Thiazoles chemistry Protein Tyrosine Phosphatases |
| Zdroj: | The Journal of biological chemistry. 281(43) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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