Abstract
Acetylation1,2, phosphorylation3 and methylation4 of the amino-terminal tails of histones are thought to be involved in the regulation of chromatin structure and function5,6,7. With just one exception8,9, the enzymes identified in the methylation of specific lysine residues on histones (histone methyltransferases) belong to the SET family10. The high-resolution crystal structure of a ternary complex of human SET7/9 with a histone peptide and cofactor reveals that the peptide substrate and cofactor bind on opposite surfaces of the enzyme. The target lysine accesses the active site of the enzyme and the S-adenosyl-l-methionine (AdoMet) cofactor by inserting its side chain into a narrow channel that runs through the enzyme, connecting the two surfaces. Here we show from the structure and from solution studies that SET7/9, unlike most other SET proteins, is exclusively a mono-methylase. The structure indicates the molecular basis of the specificity of the enzyme for the histone target, and allows us to propose a model for the methylation reaction that accounts for the role of many of the residues that are invariant across the SET family.
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Acknowledgements
We are grateful to G. Dodson and S. Smerdon for critical reading of the manuscript, and to Y. Shinkai and Y. Tanaka for the gift of the G9a clone. NMR spectra were recorded at the MRC Biomedical NMR Centre.
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Xiao, B., Jing, C., Wilson, J. et al. Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature 421, 652–656 (2003). https://doi.org/10.1038/nature01378
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DOI: https://doi.org/10.1038/nature01378
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