Nat Struct Mol Biol. 2004 Aug;11(8):730-7. Epub 2004 Jul 18.

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.

Source

Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, California 94080, USA.

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.

PMID:: 15258570; [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances, Secondary Source ID, Grant Support

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Research Support, U.S. Gov't, P.H.S.

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Grant Support

R43-DK063764/DK/NIDDK NIH HHS/United States

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Cited by 20 PubMed Central articles

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Structures reported by this article

Allosteric Inhibition Of Protein Tyrosine Phosphatase 1b

PDB: 1T4J

Source: Homo sapiens

Method: X-Ray Diffraction

Resolution: 2.7 Å

See all 3 structures...

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