2MV7

Solution NMR structure of DOT1L in complex with AF9 (DOT1L-AF9)

Summary for 2MV7

• Entry DOI: 10.2210/pdb2mv7/pdb
• Related: 2LM0
• NMR Information: BMRB: 19516
• Descriptor: Protein AF-9, Histone-lysine N-methyltransferase, H3 lysine-79 specific (2 entities in total)
• Functional Keywords: mixed lineage leukemia, leukemia, protein binding-transferase complex, protein binding/transferase
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : P42568 Q8TEK3
• Total number of polymer chains: 2
• Total formula weight: 10814.33

Authors

Kuntimaddi, A.,Bushweller, J.H. (deposition date: 2014-09-24, release date: 2015-04-22, Last modification date: 2024-05-15)

Primary citation

Kuntimaddi, A.,Achille, N.J.,Thorpe, J.,Lokken, A.A.,Singh, R.,Hemenway, C.S.,Adli, M.,Zeleznik-Le, N.J.,Bushweller, J.H.
Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential.
Cell Rep, 11:808-820, 2015

PubMed Abstract: The MLL gene is a common target of chromosomal translocations found in human leukemia. MLL-fusion leukemia has a consistently poor outcome. One of the most common translocation partners is AF9 (MLLT3). MLL-AF9 recruits DOT1L, a histone 3 lysine 79 methyltransferase (H3K79me1/me2/me3), leading to aberrant gene transcription. We show that DOT1L has three AF9 binding sites and present the nuclear magnetic resonance (NMR) solution structure of a DOT1L-AF9 complex. We generate structure-guided point mutations and find that they have graded effects on recruitment of DOT1L to MLL-AF9. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses of H3K79me2 and H3K79me3 show that graded reduction of the DOT1L interaction with MLL-AF9 results in differential loss of H3K79me2 and me3 at MLL-AF9 target genes. Furthermore, the degree of DOT1L recruitment is linked to the level of MLL-AF9 hematopoietic transformation.

PubMed: 25921540
DOI: 10.1016/j.celrep.2015.04.004

Experimental method

SOLUTION NMR