Switching the Switch: Ligand Induced Disulfide Formation in HDAC8

Overview

Journal Chemistry

Specialty Chemistry

Date 2020 May 20

PMID 32428298

Citations 7

Authors

Niklas Jansch

Wisely Oki Sugiarto

Marius Muth

Aleksandra Kopranovic

Charlotte Desczyk

Matthias Ballweg

Frank Kirschhofer

Gerald Brenner-Weiss

Franz-Josef Meyer-Almes

Affiliations

Soon will be listed here.

Abstract

Human histone deacetylase 8 is a well-recognized target for T-cell lymphoma and particularly childhood neuroblastoma. PD-404,182 was shown to be a selective covalent inhibitor of HDAC8 that forms mixed disulfides with several cysteine residues and is also able to transform thiol groups to thiocyanates. Moreover, HDAC8 was shown to be regulated by a redox switch based on the reversible formation of a disulfide bond between cysteines Cys and Cys . This study on the distinct effects of PD-404,182 on HDAC8 reveals that this compound induces the dose-dependent formation of intramolecular disulfide bridges. Therefore, the inhibition mechanism of HDAC8 by PD-404,182 involves both, covalent modification of thiols as well as ligand mediated disulfide formation. Moreover, this study provides a deep molecular insight into the regulation mechanism of HDAC8 involving several cysteines with graduated capability to form reversible disulfide bridges.

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