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Switching the Switch: Ligand Induced Disulfide Formation in HDAC8

Jänsch, Niklas; Sugiarto, Wisely Oki; Muth, Marius; Kopranovic, Aleksandra; Desczyk, Charlotte; Ballweg, Matthias; Kirschhöfer, Frank; Brenner‐Weiss, Gerald; Meyer‐Almes, Franz‐Josef

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$_{102}$ 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.

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Verlagsausgabe §
DOI: 10.5445/IR/1000124433
Veröffentlicht am 12.11.2020
Originalveröffentlichung
DOI: 10.1002/chem.202001712
Scopus
Zitationen: 1
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Zitationen: 1
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Funktionelle Grenzflächen (IFG)
Publikationstyp Zeitschriftenaufsatz
Publikationsdatum 15.10.2020
Sprache Englisch
Identifikator ISSN: 0947-6539, 1521-3765
KITopen-ID: 1000124433
HGF-Programm 47.02.06 (POF III, LK 01) Zellpopul.auf Biofunk.Oberflächen IFG
Erschienen in Chemistry - a European journal
Verlag Wiley-VCH Verlag
Band 26
Heft 58
Seiten 13249-13255
Vorab online veröffentlicht am 19.05.2020
Nachgewiesen in Web of Science
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Scopus
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