We have previously characterised the histone lysine methyltransferase properties of PRDM9, a member of the PRDM family of putative transcriptional regulators. PRDM9 displays broad substrate recognition and methylates a range of histone substrates, including octamers, core histone proteins, and peptides. In the present study, we show that PRDM9 performs intramolecular automethylation on multiple lysine residues localised to a lysine-rich region on the post-SET (suppressor of variegation 3–9, enhancer of zeste and trithorax) domain. PRDM9 automethylation is abolished by a single active-site mutation, C321P, also known to disrupt interactions with S-adenosylmethionine. We have taken an initial step towards tool compound generation through rational design of a substrate-mimic, peptidic inhibitor of PRDM9 automethylation. The discovery of automethylation in PRDM9 adds a new dimension to our understanding of PRDM9 enzymology.
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Cover Image
Cover Image
The interfacial active site of the type IB GTP cyclohydrolase from Neisseria gonorrhoeae (grey and green ribbons), in complex with zinc (magenta ball) and the reaction intermediate analog and potent inhibitor 8-oxo-GTP (stick model). The structure sheds light on the complex and unique catalytic strategy of this potential antibacterial target, and offers a starting point for the design of specific inhibitors against the enzyme. For more information, please see study by Paranagama et al. in this issue, pages 1017–1039. Image provided by Manal Swairjo.
Discovery and characterisation of the automethylation properties of PRDM9
Xiaoying Koh-Stenta, Anders Poulsen, Rong Li, John Liang Kuan Wee, Perlyn Zekui Kwek, Sin Yin Chew, Jianhe Peng, Liling Wu, Ernesto Guccione, Joma Joy, Jeffrey Hill; Discovery and characterisation of the automethylation properties of PRDM9. Biochem J 15 March 2017; 474 (6): 971–982. doi: https://doi.org/10.1042/BCJ20161067
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