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| | ==Crystal structure of histone lysine methyltransferase SmyD2 in complex with the methyltransferase inhibitor sinefungin== | | ==Crystal structure of histone lysine methyltransferase SmyD2 in complex with the methyltransferase inhibitor sinefungin== |
| - | <StructureSection load='3qww' size='340' side='right' caption='[[3qww]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='3qww' size='340' side='right'caption='[[3qww]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3qww]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QWW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QWW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3qww]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QWW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QWW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SFG:SINEFUNGIN'>SFG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SFG:SINEFUNGIN'>SFG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Smyd2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Smyd2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qww FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qww OCA], [http://pdbe.org/3qww PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qww RCSB], [http://www.ebi.ac.uk/pdbsum/3qww PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qww ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3qww FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qww OCA], [https://pdbe.org/3qww PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qww RCSB], [https://www.ebi.ac.uk/pdbsum/3qww PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qww ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SMYD2_MOUSE SMYD2_MOUSE]] Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1. Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Shows even higher methyltransferase activity on p53/TP53. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates RB1 at 'Lys-860'.<ref>PMID:16805913</ref> | + | [[https://www.uniprot.org/uniprot/SMYD2_MOUSE SMYD2_MOUSE]] Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1. Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Shows even higher methyltransferase activity on p53/TP53. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates RB1 at 'Lys-860'.<ref>PMID:16805913</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | [[Category: Lk3 transgenic mice]] | | [[Category: Lk3 transgenic mice]] |
| | [[Category: Brunzelle, J]] | | [[Category: Brunzelle, J]] |
| Structural highlights
Function
[SMYD2_MOUSE] Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1. Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Shows even higher methyltransferase activity on p53/TP53. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates RB1 at 'Lys-860'.[1]
Publication Abstract from PubMed
SmyD2 belongs to a new class of chromatin regulators that control gene expression in heart development and tumorigenesis. Besides methylation of histone H3 K4, SmyD2 can methylate non-histone targets including p53 and the retinoblastoma tumor suppressor. The methyltransferase activity of SmyD proteins has been proposed to be regulated by autoinhibition via the intra- and interdomain bending of the conserved C-terminal domain (CTD). However, there has been no direct evidence of a conformational change in the CTD. Here, we report two crystal structures of SmyD2 bound either to the cofactor product S-adenosylhomocysteine or to the inhibitor sinefungin. SmyD2 has a two-lobed structure with the active site located at the bottom of a deep crevice formed between the CTD and the catalytic domain. By extensive engagement with the methyltransferase domain, the CTD stabilizes the autoinhibited conformation of SmyD2 and restricts access to the catalytic site. Unexpectedly, despite that the two SmyD2 structures are highly superimposable, significant differences are observed in the first two helices of the CTDs: the two helices bend outwards and move away from the catalytic domain to generate a less closed conformation in the sinefungin-bound structure. Although the overall fold of the individual domains is structurally conserved among SmyD proteins, SmyD2 appear to be a conformational "intermediate" between a close form of SmyD3 and an open form of SmyD1. In addition, the structures reveal that the CTD is structurally similar to tetratricopeptide repeats (TPR), a motif through which many cochaperones bind to the heat shock protein Hsp90. Our results thus provide the first evidence for the intradomain flexibility of the TPR-like CTD, which may be important for the activation of SmyD proteins by Hsp90.
Crystal structures of histone and p53 methyltransferase SmyD2 reveal a conformational flexibility of the autoinhibitory C-terminal domain.,Jiang Y, Sirinupong N, Brunzelle J, Yang Z PLoS One. 2011;6(6):e21640. Epub 2011 Jun 28. PMID:21738746[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Brown MA, Sims RJ 3rd, Gottlieb PD, Tucker PW. Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Mol Cancer. 2006 Jun 28;5:26. PMID:16805913 doi:http://dx.doi.org/10.1186/1476-4598-5-26
- ↑ Jiang Y, Sirinupong N, Brunzelle J, Yang Z. Crystal structures of histone and p53 methyltransferase SmyD2 reveal a conformational flexibility of the autoinhibitory C-terminal domain. PLoS One. 2011;6(6):e21640. Epub 2011 Jun 28. PMID:21738746 doi:10.1371/journal.pone.0021640
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