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| ==Crystal structure of mouse PRMT6 in complex with inhibitor EML736== | | ==Crystal structure of mouse PRMT6 in complex with inhibitor EML736== |
| <StructureSection load='7nue' size='340' side='right'caption='[[7nue]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='7nue' size='340' side='right'caption='[[7nue]]' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[7nue]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NUE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NUE FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NUE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NUE FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LSK:methyl+6-[5-[[~{N}-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl]carbamimidoyl]amino]pentylcarbamoylamino]-4-oxidanyl-naphthalene-2-carboxylate'>LSK</scene></td></tr> | | </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=7nue FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nue OCA], [https://pdbe.org/7nue PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nue RCSB], [https://www.ebi.ac.uk/pdbsum/7nue PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nue ProSAT]</span></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Type_I_protein_arginine_methyltransferase Type I protein arginine methyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.319 2.1.1.319] </span></td></tr>
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| <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7nue FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nue OCA], [https://pdbe.org/7nue PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nue RCSB], [https://www.ebi.ac.uk/pdbsum/7nue PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nue ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Function ==
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| [[https://www.uniprot.org/uniprot/ANM6_MOUSE ANM6_MOUSE]] Arginine methyltransferase that can catalyze the formation of both omega-N monomethylarginine (MMA) and asymmetrical dimethylarginine (aDMA), with a strong preference for the formation of aDMA. Preferentially methylates arginyl residues present in a glycine and arginine-rich domain and displays preference for monomethylated substrates. Specifically mediates the asymmetric dimethylation of histone H3 'Arg-2' to form H3R2me2a. H3R2me2a represents a specific tag for epigenetic transcriptional repression and is mutually exclusive with methylation on histone H3 'Lys-4' (H3K4me2 and H3K4me3). Acts as a transcriptional repressor of various genes such as HOXA2, THBS1 and TP53. Repression of TP53 blocks cellular senescence. Also methylates histone H2A and H4 'Arg-3' (H2AR3me and H4R3me, respectively). Acts as a regulator of DNA base excision during DNA repair by mediating the methylation of DNA polymerase beta (POLB), leading to the stimulation of its polymerase activity by enhancing DNA binding and processivity. Methylates HMGA1. Regulates alternative splicing events. Acts as a transcriptional coactivator of a number of steroid hormone receptors including ESR1, ESR2, PGR and NR3C1. Promotes fasting-induced transcriptional activation of the gluconeogenic program through methylation of the CRTC2 transcription coactivator.<ref>PMID:22904064</ref> <ref>PMID:24570487</ref>
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| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Protein arginine methyltransferases (PRMTs) are important therapeutic targets, playing a crucial role in the regulation of many cellular processes and being linked to many diseases. Yet, there is still much to be understood regarding their functions and the biological pathways in which they are involved, as well as on the structural requirements that could drive the development of selective modulators of PRMT activity. Here we report a deconstruction-reconstruction approach that, starting from a series of type I PRMT inhibitors previously identified by us, allowed for the identification of potent and selective inhibitors of PRMT4, which regardless of the low cell permeability show an evident reduction of arginine methylation levels in MCF7 cells and a marked reduction of proliferation. We also report crystal structures with various PRMTs supporting the observed specificity and selectivity.
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| Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction-Reconstruction and Fragment-Growing Approach.,Iannelli G, Milite C, Marechal N, Cura V, Bonnefond L, Troffer-Charlier N, Feoli A, Rescigno D, Wang Y, Cipriano A, Viviano M, Bedford MT, Cavarelli J, Castellano S, Sbardella G J Med Chem. 2022 Apr 28. doi: 10.1021/acs.jmedchem.2c00252. PMID:35482954<ref>PMID:35482954</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 7nue" style="background-color:#fffaf0;"></div>
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| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Type I protein arginine methyltransferase]]
| | [[Category: Bonnefond L]] |
| [[Category: Bonnefond, L]] | | [[Category: Cavarelli J]] |
| [[Category: Cavarelli, J]] | |
| [[Category: Arginine methylation]]
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| [[Category: Sam binding domain]]
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| [[Category: Transferase]]
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