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Commun Biol. 2018 Nov 2;1:183. doi: 10.1038/s42003-018-0196-2. eCollection 2018.

An asparagine/glycine switch governs product specificity of human N-terminal methyltransferase NTMT2.

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1Structural Genomics Consortium, University of Toronto, Toronto, M5G1L7 ON Canada.
2Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907 USA.
3School of Life Sciences, Jinggangshan University, 343009 Ji'an, Jiangxi China.
4Department of Physiology, University of Toronto, Toronto, M5S 1A8 ON Canada.
Contributed equally


α-N-terminal methylation of proteins is an important post-translational modification that is catalyzed by two different N-terminal methyltransferases, namely NTMT1 and NTMT2. Previous studies have suggested that NTMT1 is a tri-methyltransferase, whereas NTMT2 is a mono-methyltransferase. Here, we report the first crystal structures, to our knowledge, of NTMT2 in binary complex with S-adenosyl-L-methionine as well as in ternary complex with S-adenosyl-L-homocysteine and a substrate peptide. Our structural observations combined with biochemical studies reveal that NTMT2 is also able to di-/tri-methylate the GPKRIA peptide and di-methylate the PPKRIA peptide, otherwise it is predominantly a mono-methyltransferase. The residue N89 of NTMT2 serves as a gatekeeper residue that regulates the binding of unmethylated versus monomethylated substrate peptide. Structural comparison of NTMT1 and NTMT2 prompts us to design a N89G mutant of NTMT2 that can profoundly alter its catalytic activities and product specificities.

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