Residues in the 11 Å Channel of Histone Deacetylase 1 Promote Catalytic Activity: Implications for Designing Isoform-Selective Histone Deacetylase Inhibitors

• Published in: Journal of medicinal chemistry 2008-09, Vol.51 (18), p.5542-5551
• Main Authors: Weerasinghe, Sujith V. W, Estiu, Guillermina, Wiest, Olaf, Pflum, Mary Kay H
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Antineoplastic agents; Biological and medical sciences; Catalysis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; General aspects; Histone Deacetylase Inhibitors; Histone Deacetylases - chemistry; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Hydrolases; Isoenzymes - antagonists & inhibitors; Isoenzymes - chemistry; Isoenzymes - genetics; Isoenzymes - metabolism; Jurkat Cells; Kinetics; Medical sciences; Mutation; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800081j

Histone deacetylase 1 (HDAC1) has been linked to cell growth and cell cycle regulation, which makes it a widely recognized target for anticancer drugs. Whereas variations of the metal-binding and capping groups of HDAC inhibitors have been studied extensively, the role of the linker region is less well known, despite the potency of inhibitors with diverse linkers, such as MS-275. To facilitate a drug design that targets HDAC1, we assessed the influence of residues in the 11 Å channel of the HDAC1 active site on activity by using an alanine scan. The mutation of eight channel residues to alanine resulted in a substantial reduction in deacetylase activity. Molecular dynamics simulations indicated that alanine mutation results in significant movement of the active-site channel, which suggests that channel residues promote HDAC1 activity by influencing substrate interactions. With little characterization of HDAC1 available, the combined experimental and computational results define the active-site residues of HDAC1 that are critical for substrate/inhibitor binding and provide important insight into drug design.