8FJN

Crystal Structure of the Trypanosoma brucei DOT1A histone H3K76 methyltransferase in complex with AdoHcy - C2221 space group

8FJN の概要

• エントリーDOI: 10.2210/pdb8fjn/pdb
• 関連するPDBエントリー: 8FJM
• 分子名称: Histone-lysine N-methyltransferase, H3 lysine-79 specific, S-ADENOSYL-L-HOMOCYSTEINE, ZINC ION, ... (6 entities in total)
• 機能のキーワード: histone lysine methyltransferase, histone-modifying enzyme, dot1a, trypanosoma brucei, adohcy complex, transferase
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29851.11

構造登録者

Frisbie, V.S.,Hashimoto, H.,Debler, E.W. (登録日: 2022-12-20, 公開日: 2024-02-07, 最終更新日: 2024-09-04)

主引用文献

Frisbie, V.S.,Hashimoto, H.,Xie, Y.,De Luna Vitorino, F.N.,Baeza, J.,Nguyen, T.,Yuan, Z.,Kiselar, J.,Garcia, B.A.,Debler, E.W.
Two DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids.
Nat Commun, 15:2467-2467, 2024

PubMed Abstract: In higher eukaryotes, a single DOT1 histone H3 lysine 79 (H3K79) methyltransferase processively produces H3K79me2/me3 through histone H2B mono-ubiquitin interaction, while the kinetoplastid Trypanosoma brucei di-methyltransferase DOT1A and tri-methyltransferase DOT1B efficiently methylate the homologous H3K76 without H2B mono-ubiquitination. Based on structural and biochemical analyses of DOT1A, we identify key residues in the methyltransferase motifs VI and X for efficient ubiquitin-independent H3K76 methylation in kinetoplastids. Substitution of a basic to an acidic residue within motif VI (GxK) is essential to stabilize the DOT1A enzyme-substrate complex, while substitution of the motif X sequence VYGE by CAKS renders a rigid active-site loop flexible, implying a distinct mechanism of substrate recognition. We further reveal distinct methylation kinetics and substrate preferences of DOT1A (H3K76me0) and DOT1B (DOT1A products H3K76me1/me2) in vitro, determined by a Ser and Ala residue within motif IV, respectively, enabling DOT1A and DOT1B to mediate efficient H3K76 tri-methylation non-processively but cooperatively, and suggesting why kinetoplastids have evolved two DOT1 enzymes.

PubMed: 38503750
DOI: 10.1038/s41467-024-46637-6

実験手法

X-RAY DIFFRACTION (2.1 Å)