ArticleBiochemistry2019
Structural Basis of Catalysis and Inhibition of HDAC6 CD1, the Enigmatic Catalytic Domain of Histone Deacetylase 6.
Article in Biochemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 70 citations in OpenAlex.
- An integrated machine learning and chemical space network approach for the design of potent epigenetic HDAC6 inhibitors for targeting neurological disorders.Molecular diversity · 2026Article
- KDAC6 alters cell morphology and motility through positive and negative modulation of F-actin distribution.FEBS open bio · 2026Article
- Ferroptosis-Pyroptosis Crosstalk in Spinal Cord Injury: Molecular Mechanisms, Emerging Connectors, and Staged Therapeutic Perspectives.Journal of molecular neuroscience : MN · 2026Review
- Epigenetic Control of Stress-Induced Depression: Emerging Roles of HDAC3 and HDAC6.International journal of molecular sciences · 2026Review
- Recommended Tool Compounds: Isoform- and Class-Specific Histone Deacetylase Inhibitors.ACS pharmacology & translational science · 2026Review
- Targeting ADAMTS1/HDAC6 alleviates TGF-β1/SMAD2-associated cardiac fibrosis in cardiac fibrosis post-myocardial infarction.Cell biology and toxicology · 2026Article
- Integrated virtual screening, ADMET profiling, and molecular dynamics simulations of novel natural HDAC6 inhibitors with the potential to ameliorate skeletal muscle degeneration.Scientific reports · 2026Article
- Design and synthesis of novel HDAC6 inhibitor dimer as HDAC6 degrader for cancer treatment by palladium catalysed dimerisation.Journal of enzyme inhibition and medicinal chemistry · 2025Article
- Target Engagement Studies and Kinetic Live-Cell Degradation Assays Enable the Systematic Characterization of Histone Deacetylase 6 Degraders.ACS pharmacology & translational science · 2025Article
- Discovery of selective HDAC6 inhibitors driven by artificial intelligence and molecular dynamics simulation approaches.Journal of pharmaceutical analysis · 2025Article
- Proteomics-Based Trapping to Study Substrates of Histone Deacetylase 6 Catalytic Domain 1.Biochemistry · 2025Article
- Histones deacetylases in the epidermis: structure, functions and therapeutic implications.Frontiers in epigenetics and epigenomics · 2025Review
- The regulatory mechanisms and treatment of HDAC6 in immune dysregulation diseases.Frontiers in immunology · 2025Review
- Design, synthesis, biological andBiomedical reports · 2025Article
- Structure similarity based screening coupled to integrated structural biochemistry approach for exploring the high affinity inhibitors against histone deacetylase (HDAC)-6.In silico pharmacology · 2025Article
- Lysine deacetylase inhibitors have low selectivity in cells and exhibit predominantly off-target effects.FEBS open bio · 2025Article
- Chitosan-enclosed SLN improved SV-induced hepatocellular cell carcinoma death by modulation of IQGAP gene expression, JNK, and HDAC activities.Molecular biology reports · 2024Article
- A novel insight into neurological disorders through HDAC6 protein-protein interactions.Scientific reports · 2024Article
- Interactions of Histone Deacetylase 6 with DNA Damage Repair Factors Strengthen its Utility as a Combination Drug Target in High-Grade Serous Ovarian Cancer.ACS pharmacology & translational science · 2023Article
- Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.Nature communications · 2023Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Histone deacetylase 6 (HDAC6) is emerging as a target for inhibition in therapeutic strategies aimed at treating cancer, neurodegenerative disease, and other disorders. Among the metal-dependent HDAC isozymes, HDAC6 is unique in that it contains two catalytic domains, CD1 and CD2. CD2 is a tubulin deacetylase and a tau deacetylase, and the development of HDAC6-selective inhibitors has focused exclusively on this domain. In contrast, there is a dearth of structural and functional information regarding CD1, which exhibits much narrower substrate specificity in comparison with CD2. As the first step in addressing the CD1 information gap, we now present X-ray crystal structures of seven inhibitor complexes with wild-type, Y363F, and K330L HDAC6 CD1. These structures broaden our understanding of molecular features that are important for catalysis and inhibitor binding. The active site of HDAC6 CD1 is wider than that of CD2, which is unexpected in view of the narrow substrate specificity of CD1. Amino acid substitutions between HDAC6 CD1 and CD2, as well as conformational differences in conserved residues, define striking differences in active site contours. Catalytic activity measurements with HDAC6 CD1 confirm the preference for peptide substrates containing C-terminal acetyllysine residues. However, these measurements also show that CD1 exhibits weak activity for peptide substrates bearing certain small amino acids on the carboxyl side of the scissile acetyllysine residue. Taken together, these results establish a foundation for understanding the structural basis of HDAC6 CD1 catalysis and inhibition, pointing to possible avenues for the development of HDAC6 CD1-selective inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.