8FJM
Crystal Structure of the Trypanosoma brucei DOT1A histone H3K76 methyltransferase in complex with AdoHcy - P212121 space group
Summary for 8FJM
| Entry DOI | 10.2210/pdb8fjm/pdb |
| Descriptor | Histone-lysine N-methyltransferase, H3 lysine-79 specific, S-ADENOSYL-L-HOMOCYSTEINE, ZINC ION, ... (6 entities in total) |
| Functional Keywords | histone lysine methyltransferase, histone-modifying enzyme, dot1a, trypanosoma brucei, adohcy complex, transferase |
| Biological source | Trypanosoma brucei brucei TREU927 |
| Total number of polymer chains | 2 |
| Total formula weight | 59690.36 |
| Authors | Frisbie, V.S.,Hashimoto, H.,Debler, E.W. (deposition date: 2022-12-20, release date: 2024-02-07, Last modification date: 2024-09-04) |
| Primary citation | 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 Cited by 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: 38503750DOI: 10.1038/s41467-024-46637-6 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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