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Allosteric inhibition of protein tyrosine phosphatase 1B.

Wiesmann C, Barr KJ, Kung J, Zhu J, Erlanson DA, Shen W, Fahr BJ, Zhong M, Taylor L, Randal M, McDowell RS, Hansen SK
Nat Struct Mol Biol 11 730-7 (2004)
Related entries: 1t49, 1t4j

Cited: 261 times
EuropePMC logo PMID: 15258570

Abstract

Obesity and type II diabetes are closely linked metabolic syndromes that afflict >100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located approximately 20 A from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases.

Reviews - 1t48 mentioned but not cited (2)

  1. Cryptic binding sites on proteins: definition, detection, and druggability. Vajda S, Beglov D, Wakefield AE, Egbert M, Whitty A. Curr Opin Chem Biol 44 1-8 (2018)
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Articles - 1t48 mentioned but not cited (18)



Reviews citing this publication (36)

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Articles citing this publication (205)



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