6jn2

Crystal structure of the coiled-coil domains of human DOT1L in complex with AF10Crystal structure of the coiled-coil domains of human DOT1L in complex with AF10

Structural highlights 6jn2 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Gene: MLLT10, AF10 (HUMAN), DOT1L, KIAA1814, KMT4 (HUMAN) Activity: Histone-lysine N-methyltransferase, with EC number 2.1.1.43 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [AF10_HUMAN] Precursor T-cell acute lymphoblastic leukemia. A chromosomal aberration involving MLLT10 is associated with acute leukemias. Translocation t(10;11)(p12;q23) with KMT2A/MLL1. The result is a rogue activator protein. A chromosomal aberration involving MLLT10 is associated with diffuse histiocytic lymphomas. Translocation t(10;11)(p13;q14) with PICALM. Function [AF10_HUMAN] Probably involved in transcriptional regulation. In vitro or as fusion protein with KMT2A/MLL1 has transactivation activity. Binds to cruciform DNA. [DOT1L_HUMAN] Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA. Publication Abstract from PubMed Chromosomal translocations of MLL1 (Mixed Lineage Leukemia 1) yield oncogenic chimeric proteins containing the N-terminal portion of MLL1 fused with distinct partners. The MLL1-AF10 fusion causes leukemia through recruiting the H3K79 histone methyltransferase DOT1L via AF10's octapeptide and leucine zipper (OM-LZ) motifs. Yet, the precise interaction sites in DOT1L, detailed interaction modes between AF10 and DOT1L, and the functional configuration of MLL1-AF10 in leukeomogenesis remain unknown. Through a combined approach of structural and functional analyses, we found that the LZ domain of AF10 interacts with the coiled-coil domains of DOT1L through a conserved binding mode and discovered that the C-terminal end of the LZ domain and the OM domain of AF10 mediate the formation of a DOT1L-AF10 octamer via tetramerization of the binary complex. We reveal that the oligomerization ability of the DOT1L-AF10 complex is essential for MLL1-AF10's leukemogenic function. These findings provide insights into the molecular basis of pathogenesis by MLL1 rearrangements. A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity.,Song X, Yang L, Wang M, Gu Y, Ye B, Fan Z, Xu RM, Yang N Proc Natl Acad Sci U S A. 2019 Sep 16. pii: 1904672116. doi:, 10.1073/pnas.1904672116. PMID:31527241 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 6jn2, resolution 3.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image