Allosteric inhibition of protein tyrosine phosphatase 1B

来自 EBSCO

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143

作者：

C Wiesmann，KJ Barr，J Kung，J Zhu，Stig K Hansen

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摘要：

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.

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关键词：

Animals Humans CHO Cells Obesity Tyrosine Phosphoric Monoester Hydrolases DNA Ligands Crystallography, X-Ray Cloning, Molecular