Entropy as a Driver of Selectivity for Inhibitor Binding to Histone Deacetylase 6

Biochemistry
Nicholas J PorterDavid W Christianson

Abstract

Among the metal-dependent histone deacetylases, the class IIb isozyme HDAC6 is remarkable because of its role in the regulation of microtubule dynamics in the cytosol. Selective inhibition of HDAC6 results in microtubule hyperacetylation, leading to cell cycle arrest and apoptosis, which is a validated strategy for cancer chemotherapy and the treatment of other disorders. HDAC6 inhibitors generally consist of a Zn2+-binding group such as a hydroxamate, a linker, and a capping group; the capping group is a critical determinant of isozyme selectivity. Surprisingly, however, even "capless" inhibitors exhibit appreciable HDAC6 selectivity. To probe the chemical basis for this selectivity, we now report high-resolution crystal structures of HDAC6 complexed with capless cycloalkyl hydroxamate inhibitors 1-4. Each inhibitor hydroxamate group coordinates to the catalytic Zn2+ ion with canonical bidentate geometry. Additionally, the olefin moieties of compounds 2 and 4 bind in an aromatic crevice between the side chains of F583 and F643. Reasoning that similar binding could be achieved in the representative class I isozyme HDAC8, we employed isothermal titration calorimetry to study the thermodynamics of inhibitor binding. These measure...Continue Reading

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Citations

Aug 7, 2019·Journal of Biomolecular Structure & Dynamics·Leandro A Alves AvelarKatarina Nikolic
Sep 4, 2020·Acta Crystallographica. Section F, Structural Biology Communications·Jeremy D Osko, David W Christianson
Oct 10, 2020·European Journal of Medicinal Chemistry·Maurício T TavaresSida Shen
Nov 11, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Sravani PulyaBalaram Ghosh
Jan 12, 2021·ChemMedChem·Jelena MelesinaWolfgang Sippl
May 12, 2021·Journal of Molecular Recognition : JMR·Robert J FalconerAnthony K Mittermaier
Jan 8, 2019·ACS Medicinal Chemistry Letters·Nicholas J PorterDavid W Christianson
Aug 18, 2018·Journal of Medicinal Chemistry·Nicholas J PorterDavid W Christianson
Jul 14, 2020·ACS Chemical Biology·Corey J Herbst-GervasoniDavid W Christianson
Jan 16, 2020·ACS Medicinal Chemistry Letters·Andrew E ShouksmithPatrick T Gunning
Dec 4, 2019·Journal of Medicinal Chemistry·Jeremy D OskoDavid W Christianson
Nov 20, 2021·ACS Medicinal Chemistry Letters·Giovanni SandroneAndrea Stevenazzi

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