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| <StructureSection load='5tbi' size='340' side='right'caption='[[5tbi]], [[Resolution|resolution]] 2.29Å' scene=''> | | <StructureSection load='5tbi' size='340' side='right'caption='[[5tbi]], [[Resolution|resolution]] 2.29Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[5tbi]] is a 4 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=5TBI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TBI FirstGlance]. <br> | | <table><tr><td colspan='2'>[[5tbi]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TBI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TBI FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=78V:4-[2-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methylamino]ethylamino]-1-(methoxymethyl)pyrimidin-2-one'>78V</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PE8:3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL'>PE8</scene>, <scene name='pdbligand=SAO:5-S-[(3S)-3-AZANIUMYL-3-CARBOXYPROPYL]-5-THIOADENOSINE'>SAO</scene></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.294Å</td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Carm1, Prmt4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=78V:4-[2-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methylamino]ethylamino]-1-(methoxymethyl)pyrimidin-2-one'>78V</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PE8:3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL'>PE8</scene>, <scene name='pdbligand=SAO:5-S-[(3S)-3-AZANIUMYL-3-CARBOXYPROPYL]-5-THIOADENOSINE'>SAO</scene></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Type_I_protein_arginine_methyltransferase Type I protein arginine methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.319 2.1.1.319] </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=5tbi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tbi OCA], [https://pdbe.org/5tbi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tbi RCSB], [https://www.ebi.ac.uk/pdbsum/5tbi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tbi ProSAT]</span></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=5tbi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tbi OCA], [http://pdbe.org/5tbi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tbi RCSB], [http://www.ebi.ac.uk/pdbsum/5tbi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tbi ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/CARM1_MOUSE CARM1_MOUSE]] Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability. Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activates transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg-2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-stabilizing properties and the half-life of their target mRNAs.<ref>PMID:10381882</ref> <ref>PMID:11341840</ref> <ref>PMID:11701890</ref> <ref>PMID:11713257</ref> <ref>PMID:11983685</ref> <ref>PMID:11997499</ref> <ref>PMID:12756295</ref> <ref>PMID:14966289</ref> <ref>PMID:15186775</ref> <ref>PMID:15616592</ref> <ref>PMID:16322096</ref> <ref>PMID:17218272</ref> <ref>PMID:17882261</ref> <ref>PMID:18188184</ref> <ref>PMID:19843527</ref> <ref>PMID:19897492</ref> <ref>PMID:21138967</ref> | | [https://www.uniprot.org/uniprot/CARM1_MOUSE CARM1_MOUSE] Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability. Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activates transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg-2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-stabilizing properties and the half-life of their target mRNAs.<ref>PMID:10381882</ref> <ref>PMID:11341840</ref> <ref>PMID:11701890</ref> <ref>PMID:11713257</ref> <ref>PMID:11983685</ref> <ref>PMID:11997499</ref> <ref>PMID:12756295</ref> <ref>PMID:14966289</ref> <ref>PMID:15186775</ref> <ref>PMID:15616592</ref> <ref>PMID:16322096</ref> <ref>PMID:17218272</ref> <ref>PMID:17882261</ref> <ref>PMID:18188184</ref> <ref>PMID:19843527</ref> <ref>PMID:19897492</ref> <ref>PMID:21138967</ref> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| DNA, RNA and histone methylation is implicated in various human diseases such as cancer or viral infections, playing a major role in cell process regulation, especially in modulation of gene expression. Here we developed a convergent synthetic pathway starting from a protected bromomethylcytosine derivative to synthesize transition state analogues of the DNA methyltransferases. This approach led to seven 5-methylcytosine-adenosine compounds that were, surprisingly, inactive against hDNMT1, hDNMT3Acat, TRDMT1 and other RNA human and viral methyltransferases. Interestingly, compound 4 and its derivative 2 showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound 4 binds to the PRMT4 active site, displacing strongly the S-adenosyl-l-methionine cofactor, occupying its binding site, and interacting with the arginine substrate site through the cytosine moiety that probes the space filled by a substrate peptide methylation intermediate. Furthermore, the binding of the compounds induces important structural switches. These findings open new routes for the conception of new potent PRMT4 inhibitors based on the 5-methylcytosine-adenosine scaffold.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.
| |
| | |
| Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors.,Halby L, Marechal N, Pechalrieu D, Cura V, Franchini DM, Faux C, Alby F, Troffer-Charlier N, Kudithipudi S, Jeltsch A, Aouadi W, Decroly E, Guillemot JC, Page P, Ferroud C, Bonnefond L, Guianvarc'h D, Cavarelli J, Arimondo PB Philos Trans R Soc Lond B Biol Sci. 2018 Jun 5;373(1748). pii: rstb.2017.0072., doi: 10.1098/rstb.2017.0072. PMID:29685976<ref>PMID:29685976</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 5tbi" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
| *[[Histone methyltransferase|Histone methyltransferase]] | | *[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
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| </StructureSection> | | </StructureSection> |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Lk3 transgenic mice]] | | [[Category: Mus musculus]] |
| [[Category: Type I protein arginine methyltransferase]]
| | [[Category: Arimondo P]] |
| [[Category: Arimondo, P]] | | [[Category: Bonnefond L]] |
| [[Category: Bonnefond, L]] | | [[Category: Cavarelli J]] |
| [[Category: Cavarelli, J]] | | [[Category: Cura V]] |
| [[Category: Cura, V]] | | [[Category: Halby L]] |
| [[Category: Halby, L]] | | [[Category: Marechal N]] |
| [[Category: Marechal, N]] | | [[Category: Troffer-Charlier N]] |
| [[Category: Troffer-Charlier, N]] | |
| [[Category: Catalytic domain]]
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| [[Category: Chromatin regulator]]
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| [[Category: Mrna processing]]
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| [[Category: Mrna splicing]]
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| [[Category: Nucleus]]
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| [[Category: Protein arginine methyltransferase]]
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| [[Category: S-adenosyl-l-methionine]]
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| [[Category: Transcription]]
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| [[Category: Transcription regulation]]
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| [[Category: Transferase]]
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