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| - | {{STRUCTURE_4o6f| PDB=4o6f | SCENE= }}
| + | ==Structural Basis of Estrogen Receptor Alpha Methylation Mediated by Histone Methyltransferase SmyD2== |
| - | ===Structural Basis of Estrogen Receptor Alpha Methylation Mediated by Histone Methyltransferase SmyD2===
| + | <StructureSection load='4o6f' size='340' side='right' caption='[[4o6f]], [[Resolution|resolution]] 2.82Å' scene=''> |
| - | {{ABSTRACT_PUBMED_24594358}}
| + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[4o6f]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4O6F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4O6F FirstGlance]. <br> |
| | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=PE8:3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL'>PE8</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</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">KMT3C, SMYD2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4o6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o6f OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4o6f RCSB], [http://www.ebi.ac.uk/pdbsum/4o6f PDBsum]</span></td></tr> |
| | + | </table> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == 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. |
| | | | |
| - | ==Function==
| + | 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<ref>PMID:24594358</ref> |
| - | [[http://www.uniprot.org/uniprot/SMYD2_HUMAN 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.<ref>PMID:17108971</ref> <ref>PMID:17805299</ref> <ref>PMID:18065756</ref> <ref>PMID:20870719</ref> [[http://www.uniprot.org/uniprot/ESR1_HUMAN ESR1_HUMAN]] Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Isoform 3 can bind to ERE and inhibit isoform 1.<ref>PMID:7651415</ref> <ref>PMID:10970861</ref> <ref>PMID:9328340</ref> <ref>PMID:10681512</ref> <ref>PMID:10816575</ref> <ref>PMID:11477071</ref> <ref>PMID:11682626</ref> <ref>PMID:15078875</ref> <ref>PMID:16043358</ref> <ref>PMID:15891768</ref> <ref>PMID:16684779</ref> <ref>PMID:18247370</ref> <ref>PMID:17932106</ref> <ref>PMID:19350539</ref> <ref>PMID:20705611</ref> <ref>PMID:21937726</ref> <ref>PMID:21330404</ref> <ref>PMID:22083956</ref>
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | [[4o6f]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4O6F OCA].
| + | </div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | <ref group="xtra">PMID:024594358</ref><references group="xtra"/><references/>
| + | *[[Histone methyltransferase|Histone methyltransferase]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Human]] |
| | [[Category: Brunzelle, J.]] | | [[Category: Brunzelle, J.]] |
| | [[Category: Holcomb, J.]] | | [[Category: Holcomb, J.]] |
| Structural highlights
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jiang Y, Trescott L, Holcomb J, Zhang X, Brunzelle J, Sirinupong N, Shi X, Yang Z. Structural Insights into Estrogen Receptor alpha Methylation by Histone Methyltransferase SMYD2, a Cellular Event Implicated in Estrogen Signaling Regulation. J Mol Biol. 2014 Mar 1. pii: S0022-2836(14)00101-6. doi:, 10.1016/j.jmb.2014.02.019. PMID:24594358 doi:http://dx.doi.org/10.1016/j.jmb.2014.02.019
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