Structural Basis for the Product Specificity of Histone Lysine Methyltransferases

• Type of Material: Article
• Authors: Xing Zhang, Emory University; Zhe Yang, Emory University; Seema I. Khan, Emory University; John Horton, Emory University; Hisashi Tamaru, University of Oregon; Eric U. Selker, University of Oregon; Xiaodong Cheng, Emory University
• Language: English
• Date: 2003-07
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2003 by Cell Press
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/S1097-2765(03)00224-7
• Title of Journal or Parent Work: Molecular Cell
• ISSN: 1097-2765
• Volume: 12
• Issue: 1
• Start Page: 177
• End Page: 185
• Grant/Funding Information: These studies were supported in part by U.S. Public Health Services grants GM49245 and GM61355 (to X.Z. and X.C.) and GM35690 (to E.U.S).; National Institute of General Medical Sciences : NIGMS
• Research Categories: Chemistry, Biochemistry

Abstract

Summary 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,~4Å 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.