Charavines

Verdel, Eric

doi:10.4000/adlfi.7024

Cited by 1 publication

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“…7 Despite the common fold and catalytic mechanism shared by the catalytic domain of each HDAC isozyme, 5,[8][9][10] the HDACs have varying cellular localizations, expression patterns, client proteins, catalytic activities, and domain assemblies. 11 For example, HDAC6 12,13 is the only isozyme containing two catalytic domains, designated CD1 and CD2. 14,15 HDAC6 serves as a tubulin deacetylase in the cell cytosol and helps maintain microtubule acetylation levels that facilitate microtubule dynamics.…”

Section: Introductionmentioning

confidence: 99%

Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6

et al. 2019

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Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket.

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