OCA at 12:49, 9 May 2024

OCA — Thu, 09 May 2024 12:49:24 GMT

←Older revision		Revision as of 12:49, 9 May 2024
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-	'''Unreleased structure'''

-	~~The entry~~ 8vew is ~~ON HOLD until Paper~~ Publication	+	==Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 24==
		+	<StructureSection load='8vew' size='340' side='right'caption='[[8vew]], [[Resolution\|resolution]] 2.69Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8vew]] 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=8VEW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8VEW 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]] 2.69Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AAU:5-{2-[(2R,5S)-5-methyl-2-phenylpiperidin-1-yl](oxo)acetamido}pyridine-3-carboxamide'>A1AAU</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=8vew FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8vew OCA], [https://pdbe.org/8vew PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8vew RCSB], [https://www.ebi.ac.uk/pdbsum/8vew PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8vew 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 ==
		+	It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5.MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.

-	~~Authors~~: Whittington, D.A.	+	Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers.,Cottrell KM, Briggs KJ, Whittington DA, Jahic H, Ali JA, Davis CB, Gong S, Gotur D, Gu L, McCarren P, Tonini MR, Tsai A, Wilker EW, Yuan H, Zhang M, Zhang W, Huang A, Maxwell JP J Med Chem. 2024 Apr 25;67(8):6064-6080. doi: 10.1021/acs.jmedchem.4c00133. Epub , 2024 Apr 10. PMID:38595098<ref>PMID:38595098</ref>

-	~~Description: Crystal structure~~ of ~~PRMT5~~:~~MEP50 in complex with MTA and oxamide compound 24~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: Whittington~~, D.A~~]]	+	<div class="pdbe-citations 8vew" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Whittington DA]]

OCA at 10:40, 1 February 2024

OCA — Thu, 01 Feb 2024 10:40:06 GMT

←Older revision		Revision as of 10:40, 1 February 2024
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8vew is ON HOLD	+	The entry 8vew is ON HOLD until Paper Publication

	Authors: Whittington, D.A.		Authors: Whittington, D.A.

OCA: Protected "8vew" [edit=sysop:move=sysop]

OCA — Wed, 27 Dec 2023 22:16:45 GMT

Protected "8vew" [edit=sysop:move=sysop]

←Older revision

Revision as of 22:16, 27 December 2023

OCA: New page: '''Unreleased structure''' The entry 8vew is ON HOLD Authors: Whittington, D.A. Description: Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 24 [[Category: Un...

OCA — Wed, 27 Dec 2023 22:16:44 GMT

New page: '''Unreleased structure''' The entry 8vew is ON HOLD Authors: Whittington, D.A. Description: Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 24 [[Category: Un...

New page

'''Unreleased structure'''

The entry 8vew is ON HOLD

Authors: Whittington, D.A.

Description: Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 24
[[Category: Unreleased Structures]]
[[Category: Whittington, D.A]]

8vew - Revision history

OCA at 12:49, 9 May 2024

OCA at 10:40, 1 February 2024

OCA: Protected "8vew" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8vew is ON HOLD Authors: Whittington, D.A. Description: Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 24 [[Category: Un...