5lv3: Difference between revisions

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-'''Unreleased structure'''
-The entry 5lv3 is ON HOLD  until Paper Publication
+==Crystal structure of mouse CARM1 in complex with ligand LH1561Br==
+<StructureSection load='5lv3' size='340' side='right'caption='[[5lv3]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5lv3]] 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=5LV3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LV3 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LHF:5-[[2-[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]ethylamino]methyl]-4-azanyl-1-[2-(4-bromanylphenoxy)ethyl]pyrimidin-2-one'>LHF</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></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=5lv3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lv3 OCA], [https://pdbe.org/5lv3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lv3 RCSB], [https://www.ebi.ac.uk/pdbsum/5lv3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lv3 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[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;">
+== Publication Abstract from PubMed ==
+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'.
-Authors: Cura, V., Marechal, N., Troffer-Charlier, N., Wurtz, J.M., Bonnefond, L., Cavarelli, J.
+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>
-Description: Crystal structure of mouse CARM1 in complex with ligand LH1561Br
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Cavarelli, J]]
+<div class="pdbe-citations 5lv3" style="background-color:#fffaf0;"></div>
-[[Category: Troffer-Charlier, N]]
-[[Category: Bonnefond, L]]
+==See Also==
-[[Category: Marechal, N]]
+*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
-[[Category: Wurtz, J.M]]
+== References ==
-[[Category: Cura, V]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Mus musculus]]
+[[Category: Arimondo P]]
+[[Category: Bonnefond L]]
+[[Category: Cavarelli J]]
+[[Category: Cura V]]
+[[Category: Halby L]]
+[[Category: Marechal N]]
+[[Category: Troffer-Charlier N]]