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Allosteric inhibition of protein tyrosine phosphatase 1B.

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.

journal_name

Nat Struct Mol Biol

journal_title

Nature structural & molecular biology

authors

Wiesmann C,Barr KJ,Kung J,Zhu J,Erlanson DA,Shen W,Fahr BJ,Zhong M,Taylor L,Randal M,McDowell RS,Hansen SK

doi

10.1038/nsmb803

keywords:

subject

Has Abstract

pub_date

2004-08-01 00:00:00

pages

730-7

issue

8

eissn

1545-9993

issn

1545-9985

pii

nsmb803

journal_volume

11

pub_type

杂志文章

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