8tqz - Revision history

OCA at 08:13, 10 April 2024

OCA — Wed, 10 Apr 2024 08:13:12 GMT

←Older revision		Revision as of 08:13, 10 April 2024
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	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/EI2BA_HUMAN EI2BA_HUMAN] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.		[https://www.uniprot.org/uniprot/EI2BA_HUMAN EI2BA_HUMAN] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling downregulates translation and activates expression of stress-responsive factors that promote return to homeostasis and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions and mediating the therapeutic effects of the small-molecule ISR inhibitor ISRIB are unknown. Using hydrogen-deuterium exchange-mass spectrometry and cryo-electron microscopy, we identified a central alpha-helix whose orientation allosterically coordinates eIF2B conformation and assembly. Biochemical and cellular signaling assays show that this 'switch-helix' controls eIF2B activity and signaling. In sum, the switch-helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a conserved allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases.
-
-	A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling.,Lawrence RE, Shoemaker SR, Deal A, Sangwan S, Anand AA, Wang L, Marqusee S, Walter P Nat Chem Biol. 2023 Nov 9. doi: 10.1038/s41589-023-01453-9. PMID:37945896<ref>PMID:37945896</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 8tqz" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 08:05, 6 December 2023

OCA — Wed, 06 Dec 2023 08:05:56 GMT

←Older revision		Revision as of 08:05, 6 December 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8tqz is ~~ON HOLD until Paper~~ Publication	+	==Eukaryotic translation initiation factor 2B with a mutation (L516A) in the delta subunit==
		+	<StructureSection load='8tqz' size='340' side='right'caption='[[8tqz]], [[Resolution\|resolution]] 2.90Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8tqz]] is a 10 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=8TQZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8TQZ FirstGlance]. <br>
		+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution\|Resolution]] 2.9Å</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=8tqz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8tqz OCA], [https://pdbe.org/8tqz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8tqz RCSB], [https://www.ebi.ac.uk/pdbsum/8tqz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8tqz ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/EI2BA_HUMAN EI2BA_HUMAN] Cree leukoencephalopathy;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry.
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/EI2BA_HUMAN EI2BA_HUMAN] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling downregulates translation and activates expression of stress-responsive factors that promote return to homeostasis and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions and mediating the therapeutic effects of the small-molecule ISR inhibitor ISRIB are unknown. Using hydrogen-deuterium exchange-mass spectrometry and cryo-electron microscopy, we identified a central alpha-helix whose orientation allosterically coordinates eIF2B conformation and assembly. Biochemical and cellular signaling assays show that this 'switch-helix' controls eIF2B activity and signaling. In sum, the switch-helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a conserved allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases.

-	~~Authors~~:	+	A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling.,Lawrence RE, Shoemaker SR, Deal A, Sangwan S, Anand AA, Wang L, Marqusee S, Walter P Nat Chem Biol. 2023 Nov 9. doi: 10.1038/s41589-023-01453-9. PMID:37945896<ref>PMID:37945896</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 8tqz" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Anand A]]
		+	[[Category: Deal A]]
		+	[[Category: Lawrence R]]
		+	[[Category: Marqusee S]]
		+	[[Category: Sangwan S]]
		+	[[Category: Shoemaker S]]
		+	[[Category: Wang L]]
		+	[[Category: Watler P]]

OCA at 12:27, 20 September 2023

OCA — Wed, 20 Sep 2023 12:27:45 GMT

←Older revision		Revision as of 12:27, 20 September 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors:		Authors:

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

OCA — Wed, 16 Aug 2023 06:59:10 GMT

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

←Older revision

Revision as of 06:59, 16 August 2023

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

OCA — Wed, 16 Aug 2023 06:59:09 GMT

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

New page

'''Unreleased structure'''

The entry 8tqz is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]