Abstract
The human histone deacetylase 8 (HDAC8) is a key hydrolase in gene regulation and has been identified as a drug target for the treatment of several cancers. Previously the HDAC8 enzyme has been extensively studied using biochemical techniques, X-ray crystallography, and computational methods. Those investigations have yielded detailed information about the active site and have demonstrated that the substrate entrance surface is highly dynamic. Yet it has remained unclear how the dynamics of the entrance surface tune and influence the catalytic activity of HDAC8. Using long time scale all atom molecular dynamics simulations we have found a mechanism whereby the interactions and dynamics of two loops tune the configuration of functionally important residues of HDAC8 and could therefore influence the activity of the enzyme. We subsequently investigated this hypothesis using a well-established fluorescence activity assay and a noninvasive real-time progression assay, where deacetylation of a p53 based peptide was observed by nuclear magnetic resonance spectroscopy. Our work delivers detailed insight into the dynamic loop network of HDAC8 and provides an explanation for a number of experimental observations.
Highlights
Post-translational histone modifications are essential cellular processes that regulate the accessibility of DNA to the cell’s transcriptional apparatus
One class of enzymes that mediate the reversal of histone modifications is comprised of the histone deacetylases (HDACs),[1] which catalyze deacetylations of acetylated lysine side-chains in histones[1] and other cellular proteins.[2]
HDACs are often up-regulated in cancers,[8] and the inhibition of HDACs is believed to be a promising way to improve the treatment of several cancers.[9]
Summary
Post-translational histone modifications are essential cellular processes that regulate the accessibility of DNA to the cell’s transcriptional apparatus. One such modification is acetylation of lysine side-chains that renders these neutral in charge and thereby alters the electrostatic interactions between, for example, histone tails and DNA or bromodomains. As important as the enzymes that generate the post-translational modifications are the enzymes that reverse them. Besides histones, (de)acetylations are known to regulate a large body of enzymes in the cell,[4,5] making HDACs key entities in the regulation of eukaryotic cells.[6,7] In particular, HDACs are often up-regulated in cancers,[8] and the inhibition of HDACs is believed to be a promising way to improve the treatment of several cancers.[9]
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