Molecular Basis for the Selective Inhibition of Histone Deacetylase 6 by a Mercaptoacetamide Inhibitor

0499314 - BTÚ 2019 RIV US eng J - Journal Article
Porter, N. J. - Shen, S. - Bařinka, Cyril - Kozikowski, A. P. - Christianson, D. W.
Molecular Basis for the Selective Inhibition of Histone Deacetylase 6 by a Mercaptoacetamide Inhibitor.
ACS Medicinal Chemistry Letters. Roč. 9, č. 12 (2018), s. 1301-1305. ISSN 1948-5875
R&D Projects: GA ČR GA15-19640S; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036
Keywords : Protein crystallography * enzyme inhibitor * zinc-binding group
OECD category: Pharmacology and pharmacy
Impact factor: 3.737, year: 2018

Mercaptoacetamide histone deacetylase inhibitors are neuroprotective agents that do not exhibit the genotoxicity associated with more commonly used hydroxamate inhibitors. Here, we present the crystal structure of a selective mercaptoacetamide complexed with the C-terminal catalytic domain of HDAC6. When compared with the structure of a mercaptoacetamide bound to the class I isozyme HDAC8, different interactions are observed with the conserved tandem histidine pair in the active site. These differences likely contribute to the selectivity for inhibition of HDAC6, an important target for cancer chemotherapy and the treatment of neurodegenerative disease.
Permanent Link: http://hdl.handle.net/11104/0291546