5lsy

Structure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives

spinqualitylabelsall models 5lsy, resolution 1.62Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5lsy is a 1 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 1.62Å Ligands: 76M, SCN, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SETD2_HUMAN Histone methyltransferase that methylates 'Lys-36' of histone H3. H3 'Lys-36' methylation represents a specific tag for epigenetic transcriptional activation. Probably plays a role in chromatin structure modulation during elongation via its interaction with hyperphosphorylated POLR2A. Binds DNA at promoters. May also act as a transcription activator that binds to promoters. Binds to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression. Publication Abstract from PubMed The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods. On the basis of 2D NMR experiments comparing NSD1 and MMSET structural mobility, we designed an MMSET construct with five point mutations in the N-terminal helix of its SET domain for crystallization experiments and elucidated the structure of the mutant MMSET SET domain at 2.1 A resolution. Both NSD1 and MMSET crystal systems proved resistant to soaking or cocrystallography with inhibitors. However, use of the close homologue SETD2 as a structural surrogate supported the design and characterization of N-alkyl sinefungin derivatives, which showed low micromolar inhibition against both SETD2 and MMSET. Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.,Tisi D, Chiarparin E, Tamanini E, Pathuri P, Coyle JE, Hold A, Holding FP, Amin N, Martin AC, Rich SJ, Berdini V, Yon J, Acklam P, Burke R, Drouin L, Harmer JE, Jeganathan F, van Montfort RL, Newbatt Y, Tortorici M, Westlake M, Wood A, Hoelder S, Heightman TD ACS Chem Biol. 2016 Sep 27. PMID:27571355 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone methyltransferase 3D structures

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