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Switching the Switch: Ligand Induced Disulfide Formation in HDAC8
Author(s) -
Jänsch Niklas,
Sugiarto Wisely Oki,
Muth Marius,
Kopranovic Aleksandra,
Desczyk Charlotte,
Ballweg Matthias,
Kirschhöfer Frank,
BrennerWeiss Gerald,
MeyerAlmes FranzJosef
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202001712
Subject(s) - hdac8 , cysteine , chemistry , covalent bond , thiol , intramolecular force , ligand (biochemistry) , disulfide bond , stereochemistry , molecular switch , histone deacetylase , histone , biochemistry , molecule , enzyme , receptor , organic chemistry , gene
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 102 and Cys 153 . 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.