Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel

Ruibo Wu, Zhenyu Lu, Zexing Cao, Yingkai Zhang

Research output: Contribution to journalArticle

Abstract

It is of significant biological interest and medical importance to develop class- and isoform-selective histone deacetylase (HDAC) modulators. The impact of the linker component on HDAC inhibition specificity has been revealed but is not understood. Using Born-Oppenheimer ab initio QM/MM MD simulations, a state-of-the-art approach to simulating metallo-enzymes, we have found that the hydroxamic acid remains to be protonated upon its binding to HDAC8, and thus disproved the mechanistic hypothesis that the distinct zinc-hydroxamate chelation modes between two HDAC subclasses come from different protonation states of the hydroxamic acid. Instead, our simulations suggest a novel mechanism in which the chelation mode of hydroxamate with the zinc ion in HDACs is modulated by water access to the linker binding channel. This new insight into the interplay between the linker binding and the zinc chelation emphasizes its importance and gives guidance regarding linker design for the development of new class-IIa-specific HDAC inhibitors.

Original languageEnglish (US)
Pages (from-to)6110-6113
Number of pages4
JournalJournal of the American Chemical Society
Volume133
Issue number16
DOIs
StatePublished - Apr 27 2011

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Histone Deacetylases
Chelation
Hydroxamic Acids
Zinc
Water
Histone Deacetylase Inhibitors
Protonation
Modulators
Acids
Protein Isoforms
Ions
Enzymes

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel. / Wu, Ruibo; Lu, Zhenyu; Cao, Zexing; Zhang, Yingkai.

In: Journal of the American Chemical Society, Vol. 133, No. 16, 27.04.2011, p. 6110-6113.

Research output: Contribution to journalArticle

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