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Structure-based drug design

Opening the door to an epigenetic target

Nature Reviews Drug Discovery volume 11, pages 672–673 (2012)Cite this article

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To gain insight into why jumonji domain 3 (JMJD3) has very high specificity for H3K27me3, the authors first determined high-resolution crystal structures of histone peptides in complex with JMJD3 in the presence of cofactor analogues. This highlighted several key structural features, such as that specific histone peptide residues are important for specificity and recognition of JMJD3.

To better understand the specific residues that are important in substrate recognition and demethylase activity, the authors next mutated key residues of the H3K27me3 peptide–enzyme complex. This showed that for binding, residue R26 of the H3 peptide forms hydrogen bonds directly with residues E1244 and D1333 of JMJD3, that the P30 residue of H3 is important for demethylase activity and that the JMJD3 residues E1244, R1246, D1333 and P1388 are important for substrate recognition.

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References

ORIGINAL RESEARCH PAPER

  1. Kruidenier, L. et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488, 404–408 (2012)

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FURTHER READING

  1. Arrowsmith, C. H. et al. Epigenetic protein families: a new frontier for drug discovery. Nature Rev. Drug Discov. 11, 384–400 (2012)

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Authors
  1. Charlotte Harrison
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Harrison, C. Opening the door to an epigenetic target. Nat Rev Drug Discov 11, 672–673 (2012). https://doi.org/10.1038/nrd3827

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