Conformational Plasticity in Histone Deacetylases as a Source of New Discoveries

Histone deacetylase 3 (HDAC3) is a promising epigenetic drug target for multiple therapeutic applications. Direct and specific interaction between HDAC3 and the silencing mediator for retinoid or thyroid-hormone receptors (SMRT) is essential for enzymatic activity. The conformational plasticity of this complex and the nature of interactions with HDAC inhibitors in solution are unknown. Using novel photoreactive HDAC probes – “nanorulers”, we determined the distance between the catalytic site of the full-length HDAC3 and SMRT-DAD in solution at physiologically relevant conditions and found it to be substantially different from that predicted by the X-ray model with a 379-428aa truncated HDAC3. Further experiments indicated that in solution this distance might change in response to chemical stimuli, while the enzymatic activity remained unaffected. These observations were further validated by Saturation Transfer Difference (STD) NMR experiments. We propose that the observed changes in the distance are an important part of the histone code that remains to be explored. Mapping direct interactions and distances between macromolecules with such “nanorulers” as a function of cellular events facilitates better understanding of basic biology and ways for its manipulation in cell and tissue specific manner.