Structural Basis for the Product Specificity of Histone Lysine Methyltransferases

• Published in: Molecular cell 2003-07, Vol.12 (1), p.177-185
• Main Authors: Zhang, Xing, Yang, Zhe, Khan, Seema I., Horton, John R., Tamaru, Hisashi, Selker, Eric U., Cheng, Xiaodong
• Format: Article
• Language: English
• Subjects: Catalytic Domain - physiology; Cysteine - chemistry; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histones - chemistry; Lysine - chemistry; Macromolecular Substances; Methyltransferases - chemistry; Models, Molecular; Molecular Structure; Neurospora crassa - enzymology; Peptides - chemistry; Protein Methyltransferases; Protein Structure, Tertiary - physiology; S-Adenosylhomocysteine - chemistry; Sulfur - chemistry; Zinc - chemistry
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/S1097-2765(03)00224-7

DIM-5 is a SUV39-type histone H3 Lys9 methyltransferase that is essential for DNA methylation in N. crassa. We report the structure of a ternary complex including DIM-5, S-adenosyl- L-homocysteine, and a substrate H3 peptide. The histone tail inserts as a parallel strand between two DIM-5 strands, completing a hybrid sheet. Three post-SET cysteines coordinate a zinc atom together with Cys242 from the SET signature motif (NHX CXPN) near the active site. Consequently, a narrow channel is formed to accommodate the target Lys9 side chain. The sulfur atom of S-adenosyl- L-homocysteine, where the transferable methyl group is to be attached in S-adenosyl- L-methionine, lies at the opposite end of the channel, ∼4 Å away from the target Lys9 nitrogen. Structural comparison of the active sites of DIM-5, an H3 Lys9 trimethyltransferase, and SET7/9, an H3 Lys4 monomethyltransferase, allowed us to design substitutions in both enzymes that profoundly alter their product specificities without affecting their catalytic activities.