CDC25A-inhibitory RE derivatives bind to pocket adjacent to the catalytic site

Ayako Tsuchiya; Miwako Asanuma; Go Hirai; Kana Oonuma; Muhammad Muddassar; Eri Nishizawa; Yusuke Koyama; Yuko Otani; Kam Y. J. Zhang; Mikiko Sodeoka

doi:10.1039/C3MB00003F

CDC25A-inhibitory RE derivatives bind to pocket adjacent to the catalytic site†

Ayako Tsuchiya,^a Miwako Asanuma,^b Go Hirai,^a Kana Oonuma,^a Muhammad Muddassar,^a Eri Nishizawa,^a Yusuke Koyama,^a Yuko Otani,^a Kam Y. J. Zhang^a and Mikiko Sodeoka*^ab

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* Corresponding authors

^a RIKEN, 2-1 Hirosawa, Wako-shi, Japan
E-mail: sodeoka@riken.jp
Fax: +81 48 462 4666

^b ERATO-JST, 2-1 Hirosawa, Wako-shi, Japan

Abstract

RE derivatives, which are cell-permeable and non-electrophilic dual-specificity protein phosphatase inhibitors developed in our laboratory, inhibit CDC25A/B non-competitively, as determined by means of kinetic experiments. To identify the binding site of RE derivatives, we designed and synthesized the new probe molecule RE142, having a Michael acceptor functionality for covalent bond formation with the enzyme, a biotin tag to enable enrichment of probe-bound peptide(s), and a chemically cleavable linker to facilitate release of probe-bound peptides from avidin beads. LC-MS analysis indicated that RE142 binds to one of the residues Cys384-Tyr386 of CDC25A, within a pocket adjacent to the catalytic site.

This article is part of the themed collection: Molecular Biosystems Chemical Biology in Asia

Molecular BioSystems

CDC25A-inhibitory RE derivatives bind to pocket adjacent to the catalytic site†

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CDC25A-inhibitory RE derivatives bind to pocket adjacent to the catalytic site

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