Binding of the Microbial Cyclic Tetrapeptide Trapoxin A to the Class I Histone Deacetylase HDAC8.

ABSTRACT: Trapoxin A is a microbial cyclic tetrapeptide that is an essentially irreversible inhibitor of class I histone deacetylases (HDACs). The inhibitory warhead is the α,β-epoxyketone side-chain of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (l-Aoe), which mimics the side-chain of the HDAC substrate acetyl-l-lysine. We now report the crystal structure of the HDAC8-trapoxin A complex at 1.24 Å resolution, revealing that the ketone moiety of l-Aoe undergoes nucleophilic attack to form a zinc-bound tetrahedral gem-diolate that mimics the tetrahedral intermediate and its flanking transition states in catalysis. Mass spectrometry, activity measurements, and isothermal titration calorimetry confirm that trapoxin A binds tightly (K_d = 3 ± 1 nM) and does not covalently modify the enzyme, s

SUBMITTER: Porter NJ 

PROVIDER: S-EPMC5600712 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature