A gatekeeper residue for inhibitor sensitization of protein tyrosine phosphatases.

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Bishop AC, Blair ER

A gatekeeper residue for inhibitor sensitization of protein tyrosine phosphatases.

Bioorg Med Chem Lett. 2006 Aug 1;16(15):4002-6. Epub 2006 May 23.

PubMed ID

16716588 [ View in PubMed

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Abstract

Allele-specific enzyme inhibitors are powerful tools in chemical biology. However, few general approaches for the discovery of such inhibitors have been described. Herein is reported a method for the sensitization of protein tyrosine phosphatases (PTPs) to small-molecule inhibition. It is shown that mutation of an active-site isoleucine to alanine (I219A) sensitizes PTP1B to inhibition by a class of thiophene-based inhibitors. This sensitization strategy succeeds for both 'orthogonal' inhibitors, designed to be incompatible with wild-type PTP active sites, and previously optimized wild-type PTP inhibitors. The finding that the I219A mutation sensitizes phosphatase domains to a variety of compounds suggests that isoleucine 219 may act as a 'gatekeeper' residue that can be widely exploited for the chemical-genetic analysis of PTP function.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
2-(Oxalyl-Amino)-4,5,6,7-Tetrahydro-Thieno[2,3-C]Pyridine-3-Carboxylic Acid	Tyrosine-protein phosphatase non-receptor type 1	Ki (nM)	230	N/A	N/A	Details
2-(Oxalyl-Amino)-4,5,6,7-Tetrahydro-Thieno[2,3-C]Pyridine-3-Carboxylic Acid	Tyrosine-protein phosphatase non-receptor type 1	Ki (nM)	6000	N/A	N/A	Details