7O2R

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with ITF3985

Summary for 7O2R

• Entry DOI: 10.2210/pdb7o2r/pdb
• Descriptor: Histone deacetylase 6, 3,5-bis(fluoranyl)-~{N}-oxidanyl-4-[(5-pyrimidin-2-yl-1,2,3,4-tetrazol-2-yl)methyl]benzamide, ZINC ION, ... (7 entities in total)
• Functional Keywords: histone deacetylase, complex with hydroxamate inhibitor, hydrolase
• Biological source: Danio rerio (Zebrafish, Brachydanio rerio)
• Total number of polymer chains: 1
• Total formula weight: 41686.94

Authors

Zrubek, K.,Sandrone, G.,Cukier, C.D.,Stevenazzi, A. (deposition date: 2021-03-31, release date: 2021-10-27, Last modification date: 2024-01-31)

Primary citation

Sandrone, G.,Cukier, C.D.,Zrubek, K.,Marchini, M.,Vergani, B.,Caprini, G.,Fossati, G.,Steinkuhler, C.,Stevenazzi, A.
Role of Fluorination in the Histone Deacetylase 6 (HDAC6) Selectivity of Benzohydroxamate-Based Inhibitors.
Acs Med.Chem.Lett., 12:1810-1817, 2021

PubMed Abstract: Nonselective histone deacetylase (HDAC) inhibitors show dose-limiting side effects due to the inhibition of multiple, essential HDAC subtypes that can be limited or prevented by restricting their selectivity. We herein report the crystal structures of zebrafish HDAC6 catalytic domain 2 (zHDAC6-CD2) in complex with the selective HDAC6 inhibitors ITF3756 and ITF3985 and shed light on the role of fluorination in the selectivity of benzohydroxamate-based structures over class I isoforms. The reason for the enhancement in the selectivity of the benzohydroxamate-based compounds is the presence of specific interactions between the fluorinated linker and the key residues Gly582, Ser531, and His614 of zHDAC6, which are hindered in class I HDAC isoforms by the presence of an Aspartate that replaces Ser531. These results can be used in the design and development of novel, highly selective HDAC6 inhibitors.

PubMed: 34795871
DOI: 10.1021/acsmedchemlett.1c00425

Experimental method

X-RAY DIFFRACTION (2.3 Å)