1t49
From Proteopedia
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
| - | Obesity and type II diabetes are closely linked metabolic syndromes that | + | 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== | ==Disease== | ||
| Line 17: | Line 17: | ||
[[Category: Protein-tyrosine-phosphatase]] | [[Category: Protein-tyrosine-phosphatase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Barr, K | + | [[Category: Barr, K J.]] |
| - | [[Category: Fahr, B | + | [[Category: Fahr, B J.]] |
| - | [[Category: Hansen, S | + | [[Category: Hansen, S K.]] |
[[Category: Kung, J.]] | [[Category: Kung, J.]] | ||
| - | [[Category: McDowell, R | + | [[Category: McDowell, R S.]] |
[[Category: Randal, M.]] | [[Category: Randal, M.]] | ||
[[Category: Shen, W.]] | [[Category: Shen, W.]] | ||
| Line 33: | Line 33: | ||
[[Category: protein tyrosine phosphatase 1b]] | [[Category: protein tyrosine phosphatase 1b]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:09:41 2008'' |
Revision as of 13:09, 21 February 2008
|
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
1T49 is a Single protein structure of sequence from Homo sapiens with and as ligands. 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 Thu Feb 21 15:09:41 2008
