7d45: Difference between revisions
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==== | ==eIF2B-eIF2(aP), aP1 complex== | ||
<StructureSection load='7d45' size='340' side='right'caption='[[7d45]]' scene=''> | <StructureSection load='7d45' size='340' side='right'caption='[[7d45]], [[Resolution|resolution]] 3.80Å' 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'>[[7d45]] is a 11 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=7D45 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D45 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=7d45 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d45 OCA], [https://pdbe.org/7d45 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d45 RCSB], [https://www.ebi.ac.uk/pdbsum/7d45 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d45 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.8Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=7d45 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d45 OCA], [https://pdbe.org/7d45 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d45 RCSB], [https://www.ebi.ac.uk/pdbsum/7d45 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d45 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/EI2BB_HUMAN EI2BB_HUMAN] Cree leukoencephalopathy;Juvenile or adult CACH syndrome;Congenital or early infantile CACH syndrome;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/EI2BB_HUMAN EI2BB_HUMAN] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(alphaP). ISRIB and eIF2(alphaP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(alphaP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(alphaP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(alphaP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(alphaP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2alpha during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(alphaP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR. | |||
ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.,Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D Mol Cell. 2021 Jan 7;81(1):88-103.e6. doi: 10.1016/j.molcel.2020.10.031. Epub , 2020 Nov 20. PMID:33220178<ref>PMID:33220178</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7d45" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Eukaryotic initiation factor 3D structures|Eukaryotic initiation factor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Ito T]] | ||
[[Category: Kashiwagi K]] | |||
Latest revision as of 14:26, 30 October 2024
eIF2B-eIF2(aP), aP1 complexeIF2B-eIF2(aP), aP1 complex
Structural highlights
DiseaseEI2BB_HUMAN Cree leukoencephalopathy;Juvenile or adult CACH syndrome;Congenital or early infantile CACH syndrome;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry. FunctionEI2BB_HUMAN Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. Publication Abstract from PubMedThe small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(alphaP). ISRIB and eIF2(alphaP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(alphaP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(alphaP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(alphaP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(alphaP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2alpha during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(alphaP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR. ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.,Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D Mol Cell. 2021 Jan 7;81(1):88-103.e6. doi: 10.1016/j.molcel.2020.10.031. Epub , 2020 Nov 20. PMID:33220178[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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