1t4j
From Proteopedia
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Allosteric Inhibition of Protein Tyrosine Phosphatase 1B
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[176885], Insulin resistance, susceptibility to OMIM:[176885]
About this Structure
1T4J is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Protein-tyrosine-phosphatase, with EC number 3.1.3.48 Full crystallographic information is available from OCA.
Reference
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. 2004 Aug;11(8):730-7. Epub 2004 Jul 18. PMID:15258570
Page seeded by OCA on Fri Feb 15 16:55:15 2008
