4o6f

Structural Basis of Estrogen Receptor Alpha Methylation Mediated by Histone Methyltransferase SmyD2

spinqualitylabelsall models 4o6f, resolution 2.82Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4o6f is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NI, PE8, SAH, 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 Estrogen receptor (ER) signaling plays a pivotal role in many developmental processes and has been implicated in numerous diseases including cancers. We recently showed that direct ERalpha methylation by the multi-specificity histone lysine methyltransferase SMYD2 regulates estrogen signaling through repressing ERalpha-dependent transactivation. However, the mechanism controlling the specificity of the SMYD2-ERalpha interaction and the structural basis of SMYD2 substrate binding diversity are unknown. Here we present the crystal structure of SMYD2 in complex with a target lysine (Lys266)-containing ERalpha peptide. The structure reveals that ERalpha binds SMYD2 in a U-shaped conformation with the binding specificity determined mainly by residues C-terminal to the target lysine. The structure also reveals numerous intrapeptide contacts that ensure shape complementarity between the substrate and the active site of the enzyme, thereby likely serving as an additional structural determinant of substrate specificity. In addition, comparison of the SMYD2-ERalpha and SMYD2-p53 structures provides the first structural insight into the diverse nature of SMYD2 substrate recognition and suggests that the broad specificity of SMYD2 is achieved by multiple molecular mechanisms such as distinct peptide binding modes and the intrinsic dynamics of peptide ligands. Strikingly, a novel potentially SMYD2-specific polyethylene glycol binding site is identified in the CTD domain, implicating possible functions in extended substrate binding or protein-protein interactions. Our study thus provides the structural basis for the SMYD2-mediated ERalpha methylation, and the resulting knowledge of SMYD2 substrate specificity and target binding diversity could have important implications in selective drug design against a wide range of ERalpha-related diseases. Structural Insights into Estrogen Receptor alpha Methylation by Histone Methyltransferase SMYD2, a Cellular Event Implicated in Estrogen Signaling Regulation.,Jiang Y, Trescott L, Holcomb J, Zhang X, Brunzelle J, Sirinupong N, Shi X, Yang Z J Mol Biol. 2014 Mar 1. pii: S0022-2836(14)00101-6. doi:, 10.1016/j.jmb.2014.02.019. PMID:24594358 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone methyltransferase 3D structures

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