Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/37357
Title: Insights into the activation mechanism of class I HDAC complexes by inositol phosphates
Authors: Watson, Peter J.
Millard, Christopher J.
Riley, Andrew M.
Robertson, Naomi S.
Wright, Lyndsey C.
Godage, Himali Y.
Cowley, Shaun M.
Jamieson, Andrew G.
Potter, Barry V. L.
Schwabe, John W. R.
First Published: 25-Apr-2016
Citation: Nature Communications, 2016, 7:11262
Abstract: Histone deacetylases (HDACs) 1, 2 & 3 form the catalytic subunit of several large transcriptional repression complexes. Unexpectedly, the enzymatic activity of HDACs in these complexes has been shown to be regulated by inositol phosphates, which bind in a pocket sandwiched between the HDAC and corepressor proteins. However, the actual mechanism of activation remains poorly understood. Here we have elucidated the stereo chemical requirements for binding and activation by inositol phosphates, demonstrating that activation requires three adjacent phosphate groups and that other positions on the inositol ring can tolerate bulky substituents. We also demonstrate that there is allosteric commu nication between the inositol binding site and the active site. The crystal structure of the HDAC1:MTA1 complex bound to a novel peptide-based inhibitor and to inositol hexaphosphate suggests the molecular basis of substrate recognition, and an entropically driven allosteric mechanism of activation.
DOI Link: 10.1038/ncomms11262
eISSN: 2041-1723
Links: http://www.nature.com/ncomms/2016/160425/ncomms11262/full/ncomms11262.html
http://hdl.handle.net/2381/37357
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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