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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.

Authors :
Ala PJ
Gonneville L
Hillman MC
Becker-Pasha M
Wei M
Reid BG
Klabe R
Yue EW
Wayland B
Douty B
Polam P
Wasserman Z
Bower M
Combs AP
Burn TC
Hollis GF
Wynn R
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.

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