1g7f
HUMAN PTP1B CATALYTIC DOMAIN COMPLEXED WITH PNU177496
|
OverviewOverview
Protein tyrosine phosphatase 1B (PTP1B) attenuates insulin signaling by, catalyzing dephosphorylation of insulin receptors (IR) and is an, attractive target of potential new drugs for treating the insulin, resistance that is central to type II diabetes. Several analogues of, cholecystokinin(26)(-)(33) (CCK-8) were found to be surprisingly potent, inhibitors of PTP1B, and a common N-terminal tripeptide, N-acetyl-Asp-Tyr(SO(3)H)-Nle-, was shown to be necessary and sufficient, for inhibition. This tripeptide was modified to reduce size and peptide, character, and to replace the metabolically unstable sulfotyrosyl group., This led to the discovery of a novel phosphotyrosine bioisostere, 2-carboxymethoxybenzoic acid, and to analogues that were >100-fold more, potent than the CCK-8 analogues and >10-fold selective for PTP1B over two, other PTP enzymes (LAR and SHP-2), a dual specificity phosphatase, (cdc25b), and a serine/threonine phosphatase (calcineurin). These, inhibitors disrupted the binding of PTP1B to activated IR in vitro and, prevented the loss of tyrosine kinase (IRTK) activity that accompanied, PTP1B-catalyzed dephosphorylation of IR. Introduction of these poorly cell, permeant inhibitors into insulin-treated cells by microinjection (oocytes), or by esterification to more lipophilic proinhibitors (3T3-L1 adipocytes, and L6 myocytes) resulted in increased potency, but not efficacy, of, insulin. In some instances, PTP1B inhibitors were insulin-mimetic, suggesting that in unstimulated cells PTP1B may suppress basal IRTK, activity. X-ray crystallography of PTP1B-inhibitor complexes revealed that, binding of an inhibitor incorporating phenyl-O-malonic acid as a, phosphotyrosine bioisostere occurred with the mobile WPD loop in the open, conformation, while a closely related inhibitor with a, 2-carboxymethoxybenzoic acid bioisostere bound with the WPD loop closed, perhaps accounting for its superior potency. These CCK-derived, peptidomimetic inhibitors of PTP1B represent a novel template for further, development of potent, selective inhibitors, and their cell activity, further justifies the selection of PTP1B as a therapeutic target.
DiseaseDisease
Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[176885], Insulin resistance, susceptibility to OMIM:[176885]
About this StructureAbout this Structure
1G7F is a Single protein structure of sequence from Homo sapiens with INZ as ligand. Active as Protein-tyrosine-phosphatase, with EC number 3.1.3.48 Full crystallographic information is available from OCA.
ReferenceReference
Small molecule peptidomimetics containing a novel phosphotyrosine bioisostere inhibit protein tyrosine phosphatase 1B and augment insulin action., Bleasdale JE, Ogg D, Palazuk BJ, Jacob CS, Swanson ML, Wang XY, Thompson DP, Conradi RA, Mathews WR, Laborde AL, Stuchly CW, Heijbel A, Bergdahl K, Bannow CA, Smith CW, Svensson C, Liljebris C, Schostarez HJ, May PD, Stevens FC, Larsen SD, Biochemistry. 2001 May 15;40(19):5642-54. PMID:11341829
Page seeded by OCA on Mon Nov 12 17:01:28 2007