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

Kunze, MB; Wright, DW; Werbeck, ND; Kirkpatrick, J; Coveney, PV; Hansen, DF; (2013) Loop interactions and dynamics tune the enzymatic activity of the human histone deacetylase 8. J Am Chem Soc , 135 (47) 17862 - 17868. 10.1021/ja408184x. Green open access

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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.

Type: Article
Title: Loop interactions and dynamics tune the enzymatic activity of the human histone deacetylase 8.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/ja408184x
Publisher version: http://dx.doi.org/10.1021/ja408184x
Language: English
Additional information: Copyright © 2013 American Chemical Society ACS AuthorChoice - Terms of Use CC-BY PMCID: PMC3926704
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1426600
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