Download MendeleyChemogenetic analysis of human protein methyltransferases.
Richon, V.M., Johnston, D., Sneeringer, C.J., Jin, L., Majer, C.R., Elliston, K., Jerva, L.F., Scott, M.P., Copeland, R.A.(2011) Chem Biol Drug Des 78: 199-210
- PubMed: 21564555
- DOI: https://doi.org/10.1111/j.1747-0285.2011.01135.x
- Primary Citation of Related Structures:
3QOW, 3QOX - PubMed Abstract:
A survey of the human genome was performed to understand the constituency of protein methyltransferases (both protein arginine and lysine methyltransferases) and the relatedness of their catalytic domains. We identified 51 protein lysine methyltransferase proteins based on similarity to the canonical Drosophila Su(var)3-9, enhancer of zeste (E(z)), and trithorax (trx) domain. Disruptor of telomeric silencing-1-like, a known protein lysine methyltransferase, did not fit within the protein lysine methyltransferase family, but did group with the protein arginine methyltransferases, along with 44 other proteins, including the METTL and NOP2/Sun domain family proteins. We show that a representative METTL, METTL11A, demonstrates catalytic activity as a histone methyltransferase. We also solved the co-crystal structures of disruptor of telomeric silencing-1-like with S-adenosylmethionine and S-adenosylhomocysteine bound in its active site. The conformation of both ligands is virtually identical to that found in known protein arginine methyltransferases, METTL and NOP2/Sun domain family proteins and is distinct from that seen in the Drosophila Su(var)3-9, enhancer of zeste (E(z)), and trithorax (trx) domain protein lysine methyltransferases. We have developed biochemical assays for 11 members of the protein methyltransferase target class and have profiled the affinity of three ligands for these enzymes: the common methyl-donating substrate S-adenosylmethionine; the common reaction product S-adenosylhomocysteine; and the natural product sinefungin. The affinity of each of these ligands is mapped onto the family trees of the protein lysine methyltransferases and protein arginine methyltransferases to reveal patterns of ligand recognition by these enzymes.
Organizational Affiliation:
Epizyme, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA Genstruct Inc., One Alewife Center, Cambridge, MA 02140, USA.
