Structure, mechanism, and inhibition of the zinc-dependent histone deacetylases
| Autor: | Nicholas J. Porter, David W. Christianson |
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| Rok vydání: | 2019 |
| Předmět: |
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Molecular Lysine Molecular Conformation Quantitative Structure-Activity Relationship Plasma protein binding Isozyme Catalysis Histone Deacetylases Article Substrate Specificity 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Structural Biology Humans Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology Hydrolysis Active site Fatty acid Amides Histone Deacetylase Inhibitors Isoenzymes Zinc Histone Biochemistry chemistry Multigene Family Acetyllysine biology.protein Polyamine 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Curr Opin Struct Biol |
| ISSN: | 0959-440X |
| Popis: | Zinc-dependent histone deacetylases (HDACs) regulate the biological function of histone and non-histone proteins through the hydrolysis of acetyllysine side chains to yield free lysine and acetate. Certain HDAC isozymes exhibit alternative catalytic activities, such as polyamine deacetylase or lysine fatty acid deacylase activity. To date, crystal structures have been reported for class I HDACs (1, 2, 3, and 8), class IIa HDACs (4 and 7), and class IIb HDACs (6 and 10). Conserved active site residues mediate the chemistry of substrate activation and hydrolysis in these isozymes through a metal-activated water molecule assisted by general base-general acid catalysis. Upregulated HDAC activity is observed in cancer and neurodegenerative disease, and four HDAC inhibitors are currently approved for use in cancer chemotherapy. Crystal structures of HDAC-inhibitor complexes guide the design of new inhibitors with high affinity and selectivity for specific HDAC isozymes implicated in human disease. |
| Databáze: | OpenAIRE |
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