3qow | pdb_00003qow
DOT1L Structure in complex with SAM
Structural highlights
Function[DOT1L_HUMAN] Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA. Publication Abstract from PubMedA survey of the human genome was performed to understand the constituency of protein methyltransferases (PMTs; both protein arginine (PRMTs) and lysine (PKMTs) methyltransferases) and the relatedness of their catalytic domains. We identified 51 PKMT proteins based on similarity to the canonical SET-domain. DOT1L, a known PKMT, did not fit within the PKMT family, but did group with the PRMTs, along with 44 other proteins, including the METTL and NSUN proteins. We show that a representative METTL, METTL11A, demonstrates catalytic activity as a histone methyltransferase. We also solved the co-crystal structures of DOT1L with SAM and SAH bound in its active site. The conformation of both ligands is virtually identical to that found in known PRMTs, METTL and NSUN proteins, and is distinct from that seen in the SET domain PKMTs. We have developed biochemical assays for 11 members of the PMT target class and have profiled the affinity of three ligands for these enzymes: the common methyl-donating substrate S-adenosylmethionime (SAM); the common reaction product S-adenosylhomocysteine (SAH); and the natural product sinefungin. The affinity of each of these ligands is mapped onto the family trees of the PKMTs and PRMTs to reveal patterns of ligand recognition by these enzymes. Chemogenetic Analysis of Human Protein Methyltransferases.,Richon VM, Johnston D, Sneeringer CJ, Jin L, Majer CR, Elliston K, Fred Jerva L, Scott MP, Copeland RA Chem Biol Drug Des. 2011 May 12. doi: 10.1111/j.1747-0285.2011.01135.x. PMID:21564555[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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