MS 5O 4 Crystal structure of HDAC 6 : insights into molecular assembly , selective inhibition and microtubule deacetylation

Histone deacetylases (HDACs) form a large family of enzymes catalyzing the removal of ε-N acetyl groups from acetylated lysines on target proteins. HDACs are categorized into four classes with class I, II, and IV containing zinc-dependent enzymes (HDAC 1-11) and class III proteins using nicotine adenine dinucleotide as cofactor (SIRT 1-7) [1]. HDAC6 is a unique class II member as it is the only histone deacetylase featuring two catalytic domains and a C-terminal ubiquitin binding domain. In addition, while most HDACs are located in the nucleus acting on acetylated histone peptides, HDAC6 is mainly found in the cytosol where it regulates acetylation states of a diverse set of proteins such as tubulin, cortactin, HSP90, and many more. HDAC6 is a major regulator of the aggresome pathway, influences microtubule dynamics and the function of regulatory T-cells, and plays a role in influenza virus infection [2,3,4]. It has been shown to be involved in several cancers, neurodegenerative diseases and inflammatory processes and is actively pursued as promising drug target by pharmaceutical companies and academic groups [5]. Although several HDAC6 specific inhibitors have recently been developed by combinatorial chemistry approaches, the lack of structural information prevented further structure-based drug design and understanding of selective inhibition over other HDAC family members. Here, we present high resolution crystal structures of HDAC6 inhibitor complexes which give insight into selective inhibition and which might have the potential to enlarge the chemical inhibitor space as well as making use of completely new Zn2+ binding groups. Additional structures reveal for the first time the interdomain assembly of the two catalytic domains and the positioning of the connecting linker, while functional analyses shed light onto the role of the two catalytic domains in microtubule deacetylation and catalysis. [1] Seidel et al., Epigenomics, 2015, 7(1), 103 [2] Kawaguchi et al., Cell, 2003, 115(6), 727 [3] de Zoeten et al., MCB, 2011, 31(10), 2066 [4] Banerjee et al., Science, 2014, 346, 473 [5] Kalin and Bergman, J.Med.Chem., 56, 6297