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J Am Chem Soc. 2013 Nov 27;135(47):17862-8. doi: 10.1021/ja408184x. Epub 2013 Nov 15.

Loop interactions and dynamics tune the enzymatic activity of the human histone deacetylase 8.

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1
Institute of Structural and Molecular Biology, Division of Biosciences, University College London , Gower Street, London WC1E 6BT, United Kingdom.

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.

PMID:
24171457
PMCID:
PMC3926704
DOI:
10.1021/ja408184x
[Indexed for MEDLINE]
Free PMC Article
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