7s0u

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Current revision (16:41, 18 October 2023) (edit) (undo)
 
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==PRMT5/MEP50 crystal structure with MTA and phthalazinone fragment bound==
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<StructureSection load='7s0u' size='340' side='right'caption='[[7s0u]]' scene=''>
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<StructureSection load='7s0u' size='340' side='right'caption='[[7s0u]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7s0u]] is a 2 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=7S0U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S0U FirstGlance]. <br>
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</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=7s0u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s0u OCA], [https://pdbe.org/7s0u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s0u RCSB], [https://www.ebi.ac.uk/pdbsum/7s0u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s0u ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.01&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=81X:4-(aminomethyl)phthalazin-1(2H)-one'>81X</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>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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=7s0u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s0u OCA], [https://pdbe.org/7s0u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s0u RCSB], [https://www.ebi.ac.uk/pdbsum/7s0u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s0u ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The PRMT5*MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP-deleted cancers. Here, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective binder to the PRMT5*MTA complex and selectively inhibits PRMT5 activity in MTAP-deleted cells compared to MTAP-wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP-deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2H)-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5*MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719.
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Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5*MTA Complex for the Treatment of MTAP-Deleted Cancers.,Smith CR, Aranda R, Bobinski TP, Briere DM, Burns AC, Christensen JG, Clarine J, Engstrom LD, Gunn RJ, Ivetac A, Jean-Baptiste R, Ketcham JM, Kobayashi M, Kuehler J, Kulyk S, Lawson JD, Moya K, Olson P, Rahbaek L, Thomas NC, Wang X, Waters LM, Marx MA J Med Chem. 2022 Feb 10;65(3):1749-1766. doi: 10.1021/acs.jmedchem.1c01900. Epub , 2022 Jan 18. PMID:35041419<ref>PMID:35041419</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7s0u" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Z-disk]]
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[[Category: Gunn RJ]]
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[[Category: Ivetac A]]
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[[Category: Kulyk S]]
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[[Category: Lawson JD]]
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[[Category: Marx MA]]
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[[Category: Smith CR]]
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[[Category: Thomas NC]]

Current revision

PRMT5/MEP50 crystal structure with MTA and phthalazinone fragment bound

PDB ID 7s0u

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