3pdn

Crystal structure of SmyD3 in complex with methyltransferase inhibitor sinefungin

spinqualitylabelsall models 3pdn, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3pdn is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, MG, SFG, ZN Gene: SMYD3, ZMYND1, ZNFN3A1 (HUMAN) Activity: Histone-lysine N-methyltransferase, with EC number 2.1.1.43 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [SMYD3_HUMAN] Histone methyltransferase. Specifically methylates 'Lys-4' and 'Lys-5' of histone H3, inducing di- and tri-methylation, but not monomethylation. Plays an important role in transcriptional activation as a member of an RNA polymerase complex. Binds DNA containing 5'-CCCTCC-3' or 5'-GAGGGG-3' sequences. Publication Abstract from PubMed The SmyD family represents a new class of chromatin regulators that is important in heart and skeletal muscle development. However, the critical questions regarding how they are regulated posttranslationally remain largely unknown. We previously suggested that the histone methyltransferase activity of SmyD1, a vital myogenic regulator, appears to be regulated by autoinhibition and that the possible hinge motion of the conserved C-terminal domain (CTD) might be central to the maintenance and release of the autoinhibition. However, the lack of direct evidence of the hinge motion has limited our further understanding of this autoinhibitory mechanism. Here, we report the crystal structure of full-length SmyD3 in complex with the methyltransferase inhibitor sinefungin at 1.7 A. SmyD3 has a two-lobed structure with the substrate binding cleft located at the bottom of a 15-A-deep crevice formed between the N- and C-terminal lobes. Comparison of SmyD3 and SmyD1 clearly suggests that the CTD can undergo a large hinge-bending motion that defines two distinct conformations: SmyD3 adopts a closed conformation with the CTD partially blocking the substrate binding cleft; in contrast, SmyD1 appears to represent an open form, where the CTD swings out by approximately 12 A from the N-terminal lobe, forming an open cleft with the active site completely exposed. Overall, these findings provide novel structural insights into the mechanism that modulates the activity of the SmyD proteins and support the observation that a posttranslational activation, such as by molecular chaperon Hsp90, is required to potentiate the proteins. Structural Insights into the Autoinhibition and Posttranslational Activation of Histone Methyltransferase SmyD3.,Sirinupong N, Brunzelle J, Doko E, Yang Z J Mol Biol. 2010 Dec 15. PMID:21167177 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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