Structural Biology and Chemistry of Histone Deacetylases in Human Disease and Drug Discovery

DRA lecture held by Professor David W. Christianson, University of Pennsylvania, USA

HDAC6 is a cytosolic tubulin deacetylase that regulates microtubule dynamics; inhibition of deacetylase activity results in hyperacetylation of α-tubulin, which suppresses microtubule dynamics and leads to cell cycle arrest and apoptosis. Isozyme-specific inhibitors of HDAC6 are therefore a high priority in the search for new therapies for cancer and other diseases. Our crystal structures of HDAC6 reveal new insight on the mechanism of catalysis and inhibitor binding modes, including the binding of novel macrocyclic peptide inhibitors as well as chemically-reactive oxadiazole inhibitors. Of note, HDAC6 contains two catalytic domains, CD1 and CD2. Crystal structures interpreted in light of enzyme activity measurements reveal the identity of a "gatekeeper" responsible for the narrow substrate specificity of CD1 and broad substrate specificity of CD2. Analysis of other isozymes indicates that the related class IIb enzyme HDAC10 contains an alternative gatekeeper residue that suppresses lysine deacetylase activity altogether. Instead, HDAC10 is the cytosolic polyamine deacetylase that functions in eukaryotic polyamine metabolism.

The lecture is organised on behalf of the graduate programme in pharmaceutical sciences, Drug Research Academy, by Professor Christian A. Olsen, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen.

The DRA lecture is free of charge and open for attendance by all interested parties. It is not necessary to pre-register.