A distal regulatory region of a class I human histone deacetylase

Nicolas D. Werbeck, Vaibhav Kumar Shukla, Micha B. A. Kunze, Havva Yalinca, Ruth B. Pritchard, Lucas Siemons, Somnath Mondal, Simon O. R. Greenwood, John Kirkpatrick, Charles M. Marson and D. Flemming Hansen ()
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Nicolas D. Werbeck: University College London
Vaibhav Kumar Shukla: University College London
Micha B. A. Kunze: University College London
Havva Yalinca: University College London
Ruth B. Pritchard: University College London
Lucas Siemons: University College London
Somnath Mondal: University College London
Simon O. R. Greenwood: University College London
John Kirkpatrick: University College London
Charles M. Marson: University College London
D. Flemming Hansen: University College London

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these enzymes themselves. Here, we show that HDAC8 is allosterically regulated by shifts in populations between exchanging states. An inactive state is identified, which is stabilised by a range of mutations and resembles a sparsely-populated state in equilibrium with active HDAC8. Computational models show that the inactive and active states differ by small changes in a regulatory region that extends up to 28 Å from the active site. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, thus suggesting a general mechanism. The presented results pave the way for the development of allosteric HDAC inhibitors and regulators to improve the therapy for several disease states.

Date: 2020
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DOI: 10.1038/s41467-020-17610-w

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