9n3r
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of PRMT5:MEP50 in complex with MTA and TNG462== | |
| + | <StructureSection load='9n3r' size='340' side='right'caption='[[9n3r]], [[Resolution|resolution]] 2.47Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9n3r]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9N3R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9N3R 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]] 2.47Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BV0:~{N}-(6-azanyl-5-ethyl-pyridin-3-yl)-2-[(2~{R},5~{S})-5-methyl-2-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-5-yl]piperidin-1-yl]-2-oxidanylidene-ethanamide'>A1BV0</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MTA:5-DEOXY-5-METHYLTHIOADENOSINE'>MTA</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=9n3r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9n3r OCA], [https://pdbe.org/9n3r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9n3r RCSB], [https://www.ebi.ac.uk/pdbsum/9n3r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9n3r ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/ANM5_HUMAN ANM5_HUMAN] Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA. Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles. Methylates SUPT5H. Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. Plays a role in the assembly of snRNP core particles. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. May regulate the SUPT5H transcriptional elongation properties. May be part of a pathway that is connected to a chloride current, possibly through cytoskeletal rearrangement. Methylates histone H2A and H4 'Arg-3' during germ cell development. Methylates histone H3 'Arg-8', which may repress transcription. Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage. Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation. Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity. Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9. Methylates and regulates SRGAP2 which is involved in cell migration and differentiation. Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter.<ref>PMID:10531356</ref> <ref>PMID:11152681</ref> <ref>PMID:11747828</ref> <ref>PMID:12411503</ref> <ref>PMID:15737618</ref> <ref>PMID:17709427</ref> <ref>PMID:20159986</ref> <ref>PMID:20810653</ref> <ref>PMID:21258366</ref> <ref>PMID:21917714</ref> <ref>PMID:22269951</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10-15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials. | ||
| - | + | Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion.,Cottrell KM, Briggs KJ, Tsai A, Tonini MR, Whittington DA, Gong S, Liang C, McCarren P, Zhang M, Zhang W, Huang A, Maxwell JP J Med Chem. 2025 Mar 4. doi: 10.1021/acs.jmedchem.4c03067. PMID:40035511<ref>PMID:40035511</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Whittington | + | <div class="pdbe-citations 9n3r" style="background-color:#fffaf0;"></div> |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Whittington DA]] | ||
Current revision
Crystal structure of PRMT5:MEP50 in complex with MTA and TNG462
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