Peptides Derived from Histone 3 and Modified at Position 18 Inhibit Histone Demethylase KDM6 Enzymes. (24th July 2018)

• Record Type: Journal Article
• Authors: Jones, Sarah E.; Olsen, Lars; Dorosz, Jerzy; Seger, Signe T.; Andersson, Jan L.; Kristensen, Line H.; Gajhede, Michael
• Is Part Of: Chembiochem. Volume 19:Number 17(2018)
• Page Start: 1817
• Page End: 1822
• Publication Date: 2018-07-24
• Subjects: cancer -- epigenetics -- histone demethylases -- inhibitors -- peptides; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201800185
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: The KDM6 subfamily of histone lysine demethylases has recently been implicated as a putative target in the treatment of a number of diseases; this makes the availability of potent and selective inhibitors important. Due to high sequence similarity of the catalytic domain of Jumonji C histone demethylases, the development of small‐molecule, family‐specific inhibitors has, however, proven challenging. One approach to achieve the selective inhibition of these enzymes is the use of peptides derived from the substrate, the histone 3 C terminus. Here we used computational methods to optimize such inhibitors of the KDM6 family. Through natural amino acid substitution, it is shown that a K18I variant of a histone H3 derived peptide significantly increases affinity towards the KDM6 enzymes. The crystal structure of KDM6B in complex with a histone 3 derived K18I peptide reveals a tighter fit of the isoleucine side chain, compared with that of the arginine. As a consequence, the peptide R17 residue also has increased hydrophilic interactions. These interactions of the optimized peptide are likely to be responsible for the increased affinity to the KDM6 enzymes. Abstract : Uncovering inhibitions : Identification of high‐affinity selective histone demethylase inhibitors is challenging. Starting from the substrate‐derived peptide, a computational approach is used to identify a KDM6 sequence variant K18I that significantly increases binding affinity. The crystal structure of KDM6B in complex with the peptide can rationalize the improved binding.