OCA at 14:39, 20 September 2023

OCA — Wed, 20 Sep 2023 14:39:14 GMT

←Older revision		Revision as of 14:39, 20 September 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8bn8 is ~~ON HOLD until Paper~~ Publication	+	==METTL3-METTL14 heterodimer bound to the SAM competitive small molecule inhibitor STM3006==
		+	<StructureSection load='8bn8' size='340' side='right'caption='[[8bn8]], [[Resolution\|resolution]] 2.21Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8bn8]] 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=8BN8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BN8 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]] 2.213Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QWR:2-[[4-(6-bromanyl-2~{H}-indazol-4-yl)-1,2,3-triazol-1-yl]methyl]-6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridine'>QWR</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=8bn8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bn8 OCA], [https://pdbe.org/8bn8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bn8 RCSB], [https://www.ebi.ac.uk/pdbsum/8bn8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bn8 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/MTA70_HUMAN MTA70_HUMAN] N6-methyltransferase that methylates adenosine residues of some RNAs and acts as a regulator of the circadian clock, differentiation of embryonic stem cells and primary miRNA processing. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing, translation efficiency, editing and mRNA stability (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:9409616). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998).[UniProtKB:Q8C3P7]<ref>PMID:22575960</ref> <ref>PMID:24284625</ref> <ref>PMID:25719671</ref> <ref>PMID:25799998</ref> <ref>PMID:26321680</ref> <ref>PMID:26593424</ref> <ref>PMID:9409616</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Therapies that enhance anti-tumour immunity have altered the natural history of many cancers. Consequently, leveraging non-overlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyltransferase, METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signalling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that whilst METTL3 inhibition is equally efficacious to anti-PD1 therapy, the combination has far greater pre-clinical activity. Using SPLINTR barcoding, we demonstrate that anti-PD1 and METTL3 inhibition target distinct malignant clones and the combination of these therapies overcome clones insensitive to the single agents. These data provide the molecular and pre-clinical rationale for employing METTL3 inhibitors to promote anti-tumour immunity in the clinic.

-	~~Authors~~:	+	Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity.,Guirguis AA, Ofir-Rosenfeld Y, Knezevic K, Blackaby W, Hardick D, Chan YC, Motazedian A, Gillespie A, Vassiliadis D, Lam EY, Tran K, Andrews B, Harbour ME, Vasiliauskaite L, Saunders CJ, Tsagkogeorga G, Azevedo A, Obacz J, Pilka ES, Carkill M, MacPherson L, Wainwright EN, Liddicoat B, Blyth BJ, Albertella MR, Rausch O, Dawson MA Cancer Discov. 2023 Aug 7:CD-23-0007. doi: 10.1158/2159-8290.CD-23-0007. PMID:37548590<ref>PMID:37548590</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 8bn8" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Blackaby W]]
		+	[[Category: Feeney K]]
		+	[[Category: Hardick D]]
		+	[[Category: Pilka ES]]
		+	[[Category: Rausch O]]
		+	[[Category: Ridgill M]]
		+	[[Category: Rotty B]]
		+	[[Category: Thomas B]]

OCA at 05:58, 21 December 2022

OCA — Wed, 21 Dec 2022 05:58:09 GMT

←Older revision		Revision as of 05:58, 21 December 2022
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8bn8 is ON HOLD	+	The entry 8bn8 is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "8bn8" [edit=sysop:move=sysop]

OCA — Thu, 24 Nov 2022 07:58:34 GMT

Protected "8bn8" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:58, 24 November 2022

OCA: New page: '''Unreleased structure''' The entry 8bn8 is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Thu, 24 Nov 2022 07:58:31 GMT

New page: '''Unreleased structure''' The entry 8bn8 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 8bn8 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

8bn8 - Revision history

OCA at 14:39, 20 September 2023

OCA at 05:58, 21 December 2022

OCA: Protected "8bn8" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8bn8 is ON HOLD Authors: Description: Category: Unreleased Structures