ArticleBiochemistry2015
Variable active site loop conformations accommodate the binding of macrocyclic largazole analogues to HDAC8.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed, 56 citations in OpenAlex.
- Intrinsic structural dynamics dictate enzymatic activity and inhibition.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Crystal structure of histone deacetylase 6 complexed with (R)-lipoic acid, an essential cofactor in central carbon metabolism.The Journal of biological chemistry · 2023Article
- Crystal Structure of Histone Deacetylase 6 Complexed with (bioRxiv : the preprint server for biology · 2023Article
- Azumamides A-E: Isolation, Synthesis, Biological Activity, and Structure-Activity Relationship.Molecules (Basel, Switzerland) · 2022Review
- Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors.International journal of molecular sciences · 2022Article
- Biomaterials from the sea: Future building blocks for biomedical applications.Bioactive materials · 2021Review
- A distal regulatory region of a class I human histone deacetylase.Nature communications · 2020Article
- Structural determinants of affinity and selectivity in the binding of inhibitors to histone deacetylase 6.Bioorganic & medicinal chemistry letters · 2020Review
- Selective Inhibition of HDAC1 by Macrocyclic Polypeptide for the Treatment of Glioblastoma: A Binding Mechanistic Analysis Based on Molecular Dynamics.Frontiers in molecular biosciences · 2020Article
- Binding ofBiochemistry · 2019Article
- Structure, mechanism, and inhibition of the zinc-dependent histone deacetylases.Current opinion in structural biology · 2019Review
- Phosphorylation of Histone Deacetylase 8: Structural and Mechanistic Analysis of the Phosphomimetic S39E Mutant.Biochemistry · 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
- Process Development and Scale-up Total Synthesis of Largazole, a Potent Class I Histone Deacetylase Inhibitor.Organic process research & development · 2018Article
- Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics.Chemical reviews · 2018Review
- HDAC8 substrate selectivity is determined by long- and short-range interactions leading to enhanced reactivity for full-length histone substrates compared with peptides.The Journal of biological chemistry · 2017Article
- Active Site Metal Identity Alters Histone Deacetylase 8 Substrate Selectivity: A Potential Novel Regulatory Mechanism.Biochemistry · 2017Article
- Synthesis and Biochemical Evaluation of Biotinylated Conjugates of Largazole Analogues: Selective Class I Histone Deacetylase Inhibitors.Israel journal of chemistry · 2017Article
- Real-time monitoring of conformational transitions of single-molecule histone deacetylase 8 with nanocircuits.Chemical communications (Cambridge, England) · 2017Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
The macrocyclic depsipeptide Largazole is a potent inhibitor of metal-dependent histone deacetylases (HDACs), some of which are drug targets for cancer chemotherapy. Indeed, Largazole partially resembles Romidepsin (FK228), a macrocyclic depsipeptide already approved for clinical use. Each inhibitor contains a pendant side chain thiol that coordinates to the active site Zn(2+) ion, as observed in the X-ray crystal structure of the HDAC8-Largazole complex [Cole, K. E., Dowling, D. P., Boone, M. A., Phillips, A. J., and Christianson, D. W. (2011) J. Am. Chem. Soc. 133, 12474]. Here, we report the X-ray crystal structures of HDAC8 complexed with three synthetic analogues of Largazole in which the depsipeptide ester is replaced with a rigid amide linkage. In two of these analogues, a six-membered pyridine ring is also substituted (with two different orientations) for the five-membered thiazole ring in the macrocycle skeleton. The side chain thiol group of each analogue coordinates to the active site Zn(2+) ion with nearly ideal geometry, thereby preserving the hallmark structural feature of inhibition by Largazole. Surprisingly, in comparison with the binding of Largazole, these analogues trigger alternative conformational changes in loops L1 and L2 flanking the active site. However, despite these structural differences, inhibitory potency is generally comparable to, or just moderately less than, the inhibitory potency of Largazole. Thus, this study reveals important new structure-affinity relationships for the binding of macrocyclic inhibitors to HDAC8.
Indexed as
Identifiers
What OpenQuestion holds
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.