OCA at 16:20, 18 October 2023

2023-10-18T16:20:58Z

←Older revision		Revision as of 16:20, 18 October 2023
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-	====	+	==PRMT5:MEP50 complexed with inhibitor PF-06939999==
-	<StructureSection load='7mx7' size='340' side='right'caption='[[7mx7]]' scene=''>	+	<StructureSection load='7mx7' size='340' side='right'caption='[[7mx7]], [[Resolution\|resolution]] 2.49Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<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>	+	<table><tr><td colspan='2'>[[7mx7]] 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=7MX7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MX7 FirstGlance]. <br>
-	</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=7mx7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mx7 OCA], [https://pdbe.org/7mx7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mx7 RCSB], [https://www.ebi.ac.uk/pdbsum/7mx7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mx7 ProSAT]</span></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.49Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZR1:(1S,2S,3S,5R)-3-{[6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl]oxy}-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol'>ZR1</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=7mx7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mx7 OCA], [https://pdbe.org/7mx7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mx7 RCSB], [https://www.ebi.ac.uk/pdbsum/7mx7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mx7 ProSAT]</span></td></tr>
	</table>		</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 ==
		+	Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the cofactor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of non-small cell lung cancer (NSCLC) cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.
		+
		+	SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance.,Jensen-Pergakes K, Tatlock J, Maegley KA, McAlpine IJ, McTigue M, Xie T, Dillon CP, Wang Y, Yamazaki S, Spiegel N, Shi M, Nemeth A, Miller N, Hendrickson E, Lam H, Sherrill J, Chung CY, McMillan EA, Bryant SK, Palde P, Braganza J, Brooun A, Deng YL, Goshtasbi V, Kephart SE, Kumpf RA, Liu W, Patman RL, Rui E, Scales S, Tran-Dube M, Wang F, Wythes M, Paul TA Mol Cancer Ther. 2022 Jan;21(1):3-15. doi: 10.1158/1535-7163.MCT-21-0620. Epub , 2021 Nov 4. PMID:34737197<ref>PMID:34737197</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7mx7" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Brooun A]]
		+	[[Category: Deng YL]]
		+	[[Category: Liu W]]
		+	[[Category: McTigue M]]

OCA at 13:37, 17 November 2021

2021-11-17T13:37:24Z

←Older revision		Revision as of 13:37, 17 November 2021
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-	'''Unreleased structure'''

-	~~The entry~~ 7mx7 ~~is ON HOLD until Paper Publication~~	+	====
-		+	<StructureSection load='7mx7' size='340' side='right'caption='[[7mx7]]' scene=''>
-	~~Authors~~: ~~McTigue, M~~.~~, Deng, Y~~.L.~~, Liu, W~~.~~, Brooun, A~~.	+	== Structural highlights ==
-		+	<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>
-	~~Description~~: ~~PRMT5~~:~~MEP50 complexed with inhibitor PF-06939999~~	+	</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=7mx7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mx7 OCA], [https://pdbe.org/7mx7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mx7 RCSB], [https://www.ebi.ac.uk/pdbsum/7mx7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mx7 ProSAT]</span></td></tr>
-	[~~[Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[~~[Category~~: ~~Deng, Y~~.L]]	+	__TOC__
-	[~~[Category~~: ~~Mctigue~~, M]]	+	</StructureSection>
-	[[Category: ~~Liu, W~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Brooun, A~~]]	+	[[Category: Z-disk]]

OCA at 06:12, 25 June 2021

2021-06-25T06:12:05Z

←Older revision		Revision as of 06:12, 25 June 2021
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7mx7 is ON HOLD	+	The entry 7mx7 is ON HOLD until Paper Publication

	Authors: McTigue, M., Deng, Y.L., Liu, W., Brooun, A.		Authors: McTigue, M., Deng, Y.L., Liu, W., Brooun, A.
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	Description: PRMT5:MEP50 complexed with inhibitor PF-06939999		Description: PRMT5:MEP50 complexed with inhibitor PF-06939999
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
		+	[[Category: Deng, Y.L]]
	[[Category: Mctigue, M]]		[[Category: Mctigue, M]]
	[[Category: Liu, W]]		[[Category: Liu, W]]
-	[[Category: Deng, Y.L]]
	[[Category: Brooun, A]]		[[Category: Brooun, A]]

OCA: Protected "7mx7" [edit=sysop:move=sysop]

2021-05-26T08:01:44Z

Protected "7mx7" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:01, 26 May 2021

OCA: New page: '''Unreleased structure''' The entry 7mx7 is ON HOLD Authors: McTigue, M., Deng, Y.L., Liu, W., Brooun, A. Description: PRMT5:MEP50 complexed with inhibitor PF-06939999 [[Category: Unr...

2021-05-26T08:01:42Z

New page: '''Unreleased structure''' The entry 7mx7 is ON HOLD Authors: McTigue, M., Deng, Y.L., Liu, W., Brooun, A. Description: PRMT5:MEP50 complexed with inhibitor PF-06939999 [[Category: Unr...

New page

'''Unreleased structure'''

The entry 7mx7 is ON HOLD

Authors: McTigue, M., Deng, Y.L., Liu, W., Brooun, A.

Description: PRMT5:MEP50 complexed with inhibitor PF-06939999
[[Category: Unreleased Structures]]
[[Category: Mctigue, M]]
[[Category: Liu, W]]
[[Category: Deng, Y.L]]
[[Category: Brooun, A]]

7mx7 - Revision history

OCA at 16:20, 18 October 2023

OCA at 13:37, 17 November 2021

OCA at 06:12, 25 June 2021

OCA: Protected "7mx7" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7mx7 is ON HOLD Authors: McTigue, M., Deng, Y.L., Liu, W., Brooun, A. Description: PRMT5:MEP50 complexed with inhibitor PF-06939999 [[Category: Unr...