5VI6

Crystal structure of histone deacetylase 8 in complex with trapoxin A

Summary for 5VI6

• Entry DOI: 10.2210/pdb5vi6/pdb
• Related PRD ID: PRD_002282
• Descriptor: Histone deacetylase 8, Trapoxin A, ZINC ION, ... (7 entities in total)
• Functional Keywords: hdac, epigenetics, natural product inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 42741.02

Authors

Porter, N.J.,Christianson, D.W. (deposition date: 2017-04-14, release date: 2017-09-06, Last modification date: 2023-11-15)

Primary citation

Porter, N.J.,Christianson, D.W.
Binding of the Microbial Cyclic Tetrapeptide Trapoxin A to the Class I Histone Deacetylase HDAC8.
ACS Chem. Biol., 12:2281-2286, 2017

PubMed 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 = 3 ± 1 nM) and does not covalently modify the enzyme, so the epoxide moiety of l-Aoe remains intact. Comparison of the HDAC8-trapoxin A complex with the HDAC6-HC toxin complex provides new insight regarding the inhibitory potency of l-Aoe-containing natural products against class I and class II HDACs.

PubMed: 28846375
DOI: 10.1021/acschembio.7b00330

Experimental method

X-RAY DIFFRACTION (1.237 Å)