ArticlePloS one2011
Molecular recognition of H3/H4 histone tails by the tudor domains of JMJD2A: a comparative molecular dynamics simulations study.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed.
- The emerging roles of lysine-specific demethylase 4A in cancer: Implications in tumorigenesis and therapeutic opportunities.Genes & diseases · 2024Review
- Engineering human JMJD2A tudor domains for an improved understanding of histone peptide recognition.Proteins · 2023Article
- The COMPASS-like complex modulates fungal development and pathogenesis by regulating H3K4me3-mediated targeted gene expression in Magnaporthe oryzae.Molecular plant pathology · 2021Article
- KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches.Frontiers in oncology · 2021Review
- Unresolved Complexity in the Gene Regulatory Network Underlying EMT.Frontiers in oncology · 2020Review
- Small molecule KDM4s inhibitors as anti-cancer agents.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Understanding the Histone DNA Repair Code: H4K20me2 Makes Its Mark.Molecular cancer research : MCR · 2018Review
- High-throughput RNA sequencing reveals structural differences of orthologous brain-expressed genes between western lowland gorillas and humans.The Journal of comparative neurology · 2016Article
- Computational Analysis and Predictive Cheminformatics Modeling of Small Molecule Inhibitors of Epigenetic Modifiers.PloS one · 2016Article
- Molecular features of interaction between VEGFA and anti-angiogenic drugs used in retinal diseases: a computational approach.Frontiers in pharmacology · 2015Article
- Epigenetic control and cancer: the potential of histone demethylases as therapeutic targets.Pharmaceuticals (Basel, Switzerland) · 2012Article
- Molecular mechanisms and potential functions of histone demethylases.Nature reviews. Molecular cell biology · 2012Review
- Article
- Structural cooperativity in histone H3 tail modifications.Protein science : a publication of the Protein Society · 2011Article
- Article
- The Histone Database: an integrated resource for histones and histone fold-containing proteins.Database : the journal of biological databases and curation · 2011Article
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Authors and funding
4 authors.
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Abstract
backgroundHistone demethylase, JMJD2A, specifically recognizes and binds to methylated lysine residues at histone H3 and H4 tails (especially trimethylated H3K4 (H3K4me3), trimethylated H3K9 (H3K9me3) and di,trimethylated H4K20 (H4K20me2, H4K20me3)) via its tandem tudor domains. Crystal structures of JMJD2A-tudor binding to H3K4me3 and H4K20me3 peptides are available whereas the others are not. Complete picture of the recognition of the four histone peptides by the tandem tudor domains yet remains to be clarified. METHODOLOGY/PRINCIPAL
findingsWe report a detailed molecular dynamics simulation and binding energy analysis of the recognition of JMJD2A-tudor with four different histone tails. 25 ns fully unrestrained molecular dynamics simulations are carried out for each of the bound and free structures. We investigate the important hydrogen bonds and electrostatic interactions between the tudor domains and the peptide molecules and identify the critical residues that stabilize the complexes. Our binding free energy calculations show that H4K20me2 and H3K9me3 peptides have the highest and lowest affinity to JMJD2A-tudor, respectively. We also show that H4K20me2 peptide adopts the same binding mode with H4K20me3 peptide, and H3K9me3 peptide adopts the same binding mode with H3K4me3 peptide. Decomposition of the enthalpic and the entropic contributions to the binding free energies indicate that the recognition of the histone peptides is mainly driven by favourable van der Waals interactions. Residue decomposition of the binding free energies with backbone and side chain contributions as well as their energetic constituents identify the hotspots in the binding interface of the structures.
conclusionEnergetic investigations of the four complexes suggest that many of the residues involved in the interactions are common. However, we found two receptor residues that were related to selective binding of the H3 and H4 ligands. Modifications or mutations on one of these residues can selectively alter the recognition of the H3 tails or the H4 tails.
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