Structural basis for the product specificity of histone lysine methyltransferases.
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 (NHXCXPN) 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, approximately 4 A 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.
Zhang
Xing
X
Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA.
Yang
Zhe
Z
Khan
Seema I
SI
Horton
John R
JR
Tamaru
Hisashi
H
Selker
Eric U
EU
Cheng
Xiaodong
X
D020134:Catalytic Domain / Q000502:physiology; D003545:Cysteine / Q000737:chemistry; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry; D046911:Macromolecular Substances; D008780:Methyltransferases / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009492:Neurospora crassa / Q000201:enzymology*; D010455:Peptides / Q000737:chemistry; D011496:Protein Methyltransferases; D017434:Protein Structure, Tertiary / Q000502:physiology; D012435:S-Adenosylhomocysteine / Q000737:chemistry*; D013455:Sulfur / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
D006657:Histones; D046911:Macromolecular Substances; D010455:Peptides; D013455:Sulfur; D012435:S-Adenosylhomocysteine; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D015032:Zinc; D008239:Lysine; D003545:Cysteine