Journal Article

A distal regulatory region of a class I human histone deacetylase

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

2020

Overview

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. Human Histone Deacetylases (HDACs) regulate gene expression and are important drug targets. Here, the authors combine NMR measurements, enzymatic assays and molecular dynamics simulations and show that HDAC8 samples a catalytically active and an inactive state and further demonstrate that mutations and ligand binding alter the populations of the two states, which is of interest for inhibitor design.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 119/118 / 631/45/173 / 631/535/878/1263 / 631/57/2272/2273 / 82/6 / Allosteric properties / Allosteric Regulation / Allosteric Site / Catalytic Domain / Cloning, Molecular / Computer applications / Computer simulation / Crystallography, X-Ray / Enzyme Activation / Enzymes / Epigenetics / Escherichia coli - genetics / Escherichia coli - metabolism / Gene Expression / Genetic Vectors - chemistry / Genetic Vectors - metabolism / Histone deacetylase / Histone Deacetylase Inhibitors - chemistry / Histone Deacetylase Inhibitors - metabolism / Histone Deacetylases - chemistry / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Histones / Humanities and Social Sciences / Humans / Hydroxamic Acids - chemistry / Hydroxamic Acids - metabolism / Indoles - chemistry / Indoles - metabolism / Mathematical models / Molecular dynamics / Molecular Dynamics Simulation / multidisciplinary / Mutation / NMR / Nuclear magnetic resonance / Populations / Protein Binding / Protein Conformation, alpha-Helical / Protein Conformation, beta-Strand / Protein Interaction Domains and Motifs / Recombinant Proteins - chemistry / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Repressor Proteins - antagonists & inhibitors / Repressor Proteins - chemistry / Repressor Proteins - genetics / Repressor Proteins - metabolism / Science / Science (multidisciplinary) / Substrate Specificity / Therapeutic targets / Thermodynamics / Vorinostat - chemistry / Vorinostat - metabolism