2cmc

From Proteopedia

Revision as of 14:50, 21 February 2008

STRUCTURAL BASIS FOR INHIBITION OF PROTEIN TYROSINE PHOSPHATASE 1B BY ISOTHIAZOLIDINONE HETEROCYCLIC PHOSPHONATE MIMETICS

Overview

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.

About this Structure

2CMC is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Protein-tyrosine-phosphatase, with EC number 3.1.3.48 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics., 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, J Biol Chem. 2006 Oct 27;281(43):32784-95. Epub 2006 Aug 17. PMID:16916797

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