ArticleBiochemistry2010
Structures of metal-substituted human histone deacetylase 8 provide mechanistic inferences on biological function .
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 81 citations in OpenAlex.
- Metal Preference Hierarchy in the HDAC8 Active Site: A DFT Study.Molecules (Basel, Switzerland) · 2026Article
- Drug Discovery for Histone Deacetylase Inhibition: Past, Present and Future of Zinc-Binding Groups.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Binding mechanism and distant regulation of histone deacetylase 8 by PCI-34051.Communications biology · 2025Article
- Hit Identification and Functional Validation of Novel Dual Inhibitors of HDAC8 and Tubulin Identified by Combining Docking and Molecular Dynamics Simulations.Antioxidants (Basel, Switzerland) · 2024Article
- Distribution and diversity of classical deacylases in bacteria.Nature communications · 2024Article
- The catalytic domain of free or ligand bound histone deacetylase 4 occurs in solution predominantly in closed conformation.Protein science : a publication of the Protein Society · 2024Article
- Lysine Deacetylase Substrate Selectivity: Distinct Interaction Surfaces Drive Positive and Negative Selection for Residues Following Acetyllysine.Biochemistry · 2023Article
- How Theoretical Evaluations Can Generate Guidelines for Designing/Engineering Metalloproteins with Desired Metal Affinity and Selectivity.Molecules (Basel, Switzerland) · 2022Review
- Pathological Role of HDAC8: Cancer and Beyond.Cells · 2022Review
- Review
- Epigenetic gene regulation in plasma cells.Immunological reviews · 2021Review
- Kinetic Characterization of Human Histone Deacetylase 8 With Medium-Chain Fatty Acyl Lysine.Epigenetics insights · 2021Article
- Evidence for Quantum Chemical Effects in Receptor-Ligand Binding Between Integrin and Collagen Fragments - A Computational Investigation With an Impact on Tissue Repair, Neurooncolgy and Glycobiology.Frontiers in molecular biosciences · 2021Article
- Critical review of non-histone human substrates of metal-dependent lysine deacetylases.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Review
- Phosphorylation of Histone Deacetylase 8: Structural and Mechanistic Analysis of the Phosphomimetic S39E Mutant.Biochemistry · 2019Article
- A Genetically Encoded, Phage-Displayed Cyclic-Peptide Library.Angewandte Chemie (International ed. in English) · 2019Review
- Review
- Structurally Diverse Histone Deacetylase Photoreactive Probes: Design, Synthesis, and Photolabeling Studies in Live Cells and Tissue.ChemMedChem · 2019Article
- Preparation of a new construct of human histone deacetylase 8 for the crystallization of enzyme-inhibitor complexes.Methods in enzymology · 2019Article
- The enzyme activity of histone deacetylase 8 is modulated by a redox-switch.Redox biology · 2019Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The metal-dependent histone deacetylases (HDACs) adopt an alpha/beta protein fold first identified in rat liver arginase. Despite insignificant overall amino acid sequence identity, these enzymes share a strictly conserved metal binding site with divergent metal specificity and stoichiometry. HDAC8, originally thought to be a Zn(2+)-metallohydrolase, exhibits increased activity with Co(2+) and Fe(2+) cofactors based on k(cat)/K(M) (Gantt, S. L., Gattis, S. G., and Fierke, C. A. (2006) Biochemistry 45, 6170-6178). Here, we report the first X-ray crystal structures of metallo-substituted HDAC8, Co(2+)-HDAC8, D101L Co(2+)-HDAC8, D101L Mn(2+)-HDAC8, and D101L Fe(2+)-HDAC8, each complexed with the inhibitor M344. Metal content of protein samples in solution is confirmed by inductively coupled plasma mass spectrometry. For the crystalline enzymes, peaks in Bijvoet difference Fourier maps calculated from X-ray diffraction data collected near the respective elemental absorption edges confirm metal substitution. Additional solution studies confirm incorporation of Cu(2+); Fe(3+) and Ni(2+) do not bind under conditions tested. The metal dependence of the substrate K(M) values and the K(i) values of hydroxamate inhibitors that chelate the active site metal are consistent with substrate-metal coordination in the precatalytic Michaelis complex that enhances catalysis. Additionally, although HDAC8 binds Zn(2+) nearly 10(6)-fold more tightly than Fe(2+), the affinities for both metal ions are comparable to the readily exchangeable metal concentrations estimated in living cells, suggesting that HDAC8 could bind either or both Fe(2+) or Zn(2+) in vivo.
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Registered trials
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