7x8b

Crystal structure of ENL T1 mutant YEATS domain in complex with histone H3 acetylation at K27

spinqualitylabelsall models 7x8b, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7x8b is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: ALY Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ENL_HUMAN A chromosomal aberration involving MLLT1 is associated with acute leukemias. Translocation t(11;19)(q23;p13.3) with KMT2A/MLL1. The result is a rogue activator protein. Function ENL_HUMAN Component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. Publication Abstract from PubMed Growing evidence suggests prevalence of transcriptional condensates on chromatin, yet their mechanisms of formation and functional significance remain largely unclear. In human cancer, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation ability. Here, we show that these mutations, clustered in ENL's structured acetyl-reading YEATS domain, trigger aberrant condensates at native genomic targets through multivalent homotypic and heterotypic interactions. Mechanistically, mutation-induced structural changes in the YEATS domain, ENL's two disordered regions of opposing charges, and the incorporation of extrinsic elongation factors are all required for ENL condensate formation. Extensive mutagenesis establishes condensate formation as a driver of oncogenic gene activation. Furthermore, expression of ENL mutants beyond the endogenous level leads to non-functional condensates. Our findings provide new mechanistic and functional insights into cancer-associated condensates and support condensate dysregulation as an oncogenic mechanism. Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer.,Song L, Yao X, Li H, Peng B, Boka AP, Liu Y, Chen G, Liu Z, Mathias KM, Xia L, Li Q, Mir M, Li Y, Li H, Wan L Mol Cell. 2022 Nov 3;82(21):4080-4098.e12. doi: 10.1016/j.molcel.2022.09.034. , Epub 2022 Oct 21. PMID:36272410 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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