5kjl | pdb_00005kjl

SMYD2 in complex with AZ378

spinqualitylabelsall models 5kjl, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5kjl 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 2.7Å Ligands: SAM, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SMYD2_HUMAN Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins. Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Has also methyltransferase activity toward non-histone proteins such as p53/TP53 and RB1. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates 'Lys-860' of RB1/RB. Publication Abstract from PubMed Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes. Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors.,Cowen SD, Russell D, Dakin LA, Chen H, Larsen NA, Godin R, Throner S, Zheng X, Molina A, Wu J, Cheung T, Howard T, Garcia-Arenas R, Keen N, Pendleton CS, Pietenpol JA, Ferguson AD J Med Chem. 2016 Dec 22;59(24):11079-11097. Epub 2016 Dec 1. PMID:28002961 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone methyltransferase 3D structures

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