OCA at 20:30, 12 April 2023

OCA — Wed, 12 Apr 2023 20:30:58 GMT

←Older revision		Revision as of 20:30, 12 April 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8cyi is ~~ON HOLD until Paper~~ Publication	+	==Cryo-EM structures and computational analysis for enhanced potency in MTA-synergic inhibition of human protein arginine methyltransferase 5==
		+	<StructureSection load='8cyi' size='340' side='right'caption='[[8cyi]], [[Resolution\|resolution]] 3.14Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8cyi]] 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=8CYI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CYI FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MTA:5-DEOXY-5-METHYLTHIOADENOSINE'>MTA</scene>, <scene name='pdbligand=P2R:N-[(2-aminoquinolin-7-yl)methyl]-9-(2-hydroxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide'>P2R</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=8cyi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cyi OCA], [https://pdbe.org/8cyi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cyi RCSB], [https://www.ebi.ac.uk/pdbsum/8cyi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cyi 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 ==
		+	Projected potential of 2.5-4.0 A cryo-EM structures for structure-based drug design is not well realized yet. Here we show that a 3.1 A structure of PRMT5 is suitable for selecting computed poses of a chemical inhibitor and its analogs for enhanced potency. PRMT5, an oncogenic target for various cancer types, has many inhibitors manifesting little cooperativity with MTA, a co-factor analog accumulated in MTAP-/- cells. To achieve MTA-synergic inhibition, a pharmacophore from virtual screen leads to a specific inhibitor (11-2 F). Cryo-EM structures of 11-2 F / MTA-bound human PRMT5/MEP50 complex and its apo form resolved at 3.1 and 3.2 A respectively show that 11-2 F in the catalytic pocket shifts the cofactor-binding pocket away by ~2.0 A, contributing to positive cooperativity. Computational analysis predicts subtype specificity of 11-2 F among PRMTs. Structural analysis of ligands in the binding pockets is performed to compare poses of 11-2 F and its redesigned analogs and identifies three new analogs predicted to have significantly better potency. One of them, after synthesis, is ~4 fold more efficient in inhibiting PRMT5 catalysis than 11-2 F, with strong MTA-synergy. These data suggest the feasibility of employing near-atomic resolution cryo-EM structures and computational analysis of ligand poses for small molecule therapeutics.

-	~~Authors: Yadav, G.P~~., ~~Wei~~, Z., ~~Xiaozhi~~, Y., ~~Chenglong, L.~~, Jiang~~, Q~~.	+	Cryo-EM structure-based selection of computed ligand poses enables design of MTA-synergic PRMT5 inhibitors of better potency.,Zhou W, Yadav GP, Yang X, Qin F, Li C, Jiang QX Commun Biol. 2022 Oct 3;5(1):1054. doi: 10.1038/s42003-022-03991-9. PMID:36192627<ref>PMID:36192627</ref>

-	~~Description: Cryo~~-~~EM structures and computational analysis for enhanced potency in MTA~~-~~synergic inhibition of human protein arginine methyltransferase 5~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: ~~Jiang, Q~~]]	+	<div class="pdbe-citations 8cyi" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Wei, Z~~]]	+	== References ==
-	[[Category: ~~Xiaozhi, Y~~]]	+	<references/>
-	[[Category: ~~Chenglong, L~~]]	+	__TOC__
-	[[Category: Yadav~~, G.P~~]]	+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Chenglong L]]
		+	[[Category: Jiang Q]]
		+	[[Category: Wei Z]]
		+	[[Category: Xiaozhi Y]]
		+	[[Category: Yadav GP]]

OCA at 15:28, 7 September 2022

OCA — Wed, 07 Sep 2022 15:28:58 GMT

←Older revision		Revision as of 15:28, 7 September 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Yadav, G.P., Wei, Z., Xiaozhi, Y., Chenglong, L., Jiang, Q.		Authors: Yadav, G.P., Wei, Z., Xiaozhi, Y., Chenglong, L., Jiang, Q.

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

OCA — Wed, 08 Jun 2022 04:27:47 GMT

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

←Older revision

Revision as of 04:27, 8 June 2022

OCA: New page: '''Unreleased structure''' The entry 8cyi is ON HOLD Authors: Yadav, G.P., Wei, Z., Xiaozhi, Y., Chenglong, L., Jiang, Q. Description: Cryo-EM structures and computational analysis for...

OCA — Wed, 08 Jun 2022 04:27:46 GMT

New page: '''Unreleased structure''' The entry 8cyi is ON HOLD Authors: Yadav, G.P., Wei, Z., Xiaozhi, Y., Chenglong, L., Jiang, Q. Description: Cryo-EM structures and computational analysis for...

New page

'''Unreleased structure'''

The entry 8cyi is ON HOLD

Authors: Yadav, G.P., Wei, Z., Xiaozhi, Y., Chenglong, L., Jiang, Q.

Description: Cryo-EM structures and computational analysis for enhanced potency in MTA-synergic inhibition of human protein arginine methyltransferase 5
[[Category: Unreleased Structures]]
[[Category: Jiang, Q]]
[[Category: Wei, Z]]
[[Category: Xiaozhi, Y]]
[[Category: Chenglong, L]]
[[Category: Yadav, G.P]]

8cyi - Revision history

OCA at 20:30, 12 April 2023

OCA at 15:28, 7 September 2022

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

OCA: New page: '''Unreleased structure''' The entry 8cyi is ON HOLD Authors: Yadav, G.P., Wei, Z., Xiaozhi, Y., Chenglong, L., Jiang, Q. Description: Cryo-EM structures and computational analysis for...