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.
Whether recent updates and new releases
of atomistic force fields
can model the structural and dynamical properties of proteins containing
both folded and partially disordered domains is still unclear. To
address this fundamental question, we tested eight recently released
force fields against our set of nuclear magnetic resonance (NMR) observables
for a complex and medically relevant system, the major factor VIII
binding region on the von Willebrand factor. This biomedically important
region comprises both a folded and a partially structured domain.
By using an enhanced sampling technique (temperature replica-exchange
molecular dynamics simulations), we find that some force fields indeed
rise to the challenge and capture the structural and dynamical features
of the NMR ensemble and, therefore, are the appropriate choice for
simulations of proteins with partially structured domains. What is
more, we show that only such force fields can qualitatively capture
the effects of a pathogenic mutation on the structural ensemble.
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