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Biochemistry DOI:10.1021/acs.biochem.8b00367

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

Publication TypeJournal Article
Year of Publication2018
AuthorsPorter, NJ, Wagner, FF, Christianson, DW
JournalBiochemistry
Volume57
Issue26
Pages3916-3924
Date Published2018 07 03
ISSN1520-4995
KeywordsCrystallography, X-Ray, Entropy, Histone Deacetylase 6, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Protein Binding, Repressor Proteins
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 Zn-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 Zn 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 measurements indicate that the entropy of inhibitor binding is generally positive for binding to HDAC6 and negative for binding to HDAC8, resulting in ≤313-fold selectivity for binding to HDAC6 relative to HDAC8. Thus, favorable binding entropy contributes to HDAC6 selectivity. Notably, cyclohexenyl hydroxamate 2 represents a promising lead for derivatization with capping groups that may further enhance its impressive 313-fold thermodynamic selectivity for HDAC6 inhibition.

DOI10.1021/acs.biochem.8b00367
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29775292?dopt=Abstract

Alternate JournalBiochemistry
PubMed ID29775292
PubMed Central IDPMC6030506
Grant ListP30 EB009998 / EB / NIBIB NIH HHS / United States
P41 GM103393 / GM / NIGMS NIH HHS / United States
R01 GM049758 / GM / NIGMS NIH HHS / United States
T32 GM071339 / GM / NIGMS NIH HHS / United States