8TQ0

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with (R)-Lipoic Acid

Summary for 8TQ0

• Entry DOI: 10.2210/pdb8tq0/pdb
• Descriptor: Hdac6 protein, DIHYDROLIPOIC ACID, ZINC ION, ... (5 entities in total)
• Functional Keywords: hydrolase, histone deacetylase, inhibitor, metallohydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Danio rerio (zebrafish)
• Total number of polymer chains: 2
• Total formula weight: 81274.86

Authors

Watson, P.R.,Christianson, D.W. (deposition date: 2023-08-06, release date: 2023-09-20, Last modification date: 2024-04-03)

Primary citation

Watson, P.R.,Stollmaier, J.G.,Christianson, D.W.
Crystal structure of histone deacetylase 6 complexed with (R)-lipoic acid, an essential cofactor in central carbon metabolism.
J.Biol.Chem., 299:105228-105228, 2023

PubMed Abstract: The enzyme cofactor (R)-lipoic acid plays a critical role in central carbon metabolism due to its catalytic function in the generation of acetyl-CoA, which links glycolysis with the tricarboxylic acid cycle. This cofactor is also essential for the generation of succinyl CoA within the tricarboxylic acid cycle. However, the biological functions of (R)-lipoic acid extend beyond metabolism owing to its facile redox chemistry. Most recently, the reduced form of (R)-lipoic acid, (R)-dihydrolipoic acid, has been shown to inhibit histone deacetylases (HDACs) with selectivity for the inhibition of HDAC6. Here, we report the 2.4 Å-resolution X-ray crystal structure of the complex between (R)-dihydrolipoic acid and HDAC6 catalytic domain 2 from Danio rerio, and we report a dissociation constant (K) of 350 nM for this complex as determined by isothermal titration calorimetry. The crystal structure illuminates key affinity determinants in the enzyme active site, including thiolate-Zn coordination and S-π interactions in the F583-F643 aromatic crevice. This study provides the first visualization of the connection between HDAC function and the biological response to oxidative stress: the dithiol moiety of (R)-dihydrolipoic acid can serve as a redox-regulated pharmacophore capable of simultaneously targeting the catalytic Zn ion and the aromatic crevice in the active site of HDAC6.

PubMed: 37703993
DOI: 10.1016/j.jbc.2023.105228

Experimental method

X-RAY DIFFRACTION (2.4 Å)