Structural Basis for the Selective Inhibition of HDAC10, the Cytosolic Polyamine Deacetylase.

ABSTRACT: The cytosolic class IIb histone deacetylase HDAC10 is an emerging target for drug design. As an inducer of autophagy, its selective inhibition suppresses the autophagic response that otherwise attenuates the efficacy of cytotoxic cancer chemotherapy drugs. HDAC10 is a zinc-dependent polyamine deacetylase exhibiting maximal catalytic activity against N⁸-acetylspermidine. As revealed in the structure of Danio rerio (zebrafish) HDAC10, two conserved structural motifs direct this narrow substrate specificity: a 3₁₀ helix containing the P(E,A)CE motif that sterically constricts the active site and an electrostatic "gatekeeper," E274, that confers selectivity for cationic polyamine substrates. To accelerate drug design efforts targeting human HDAC10, we now re

SUBMITTER: Herbst-Gervasoni CJ 

PROVIDER: S-EPMC7442746 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature