View source for 6ezo


==Eukaryotic initiation factor EIF2B in complex with ISRIB==
<SX load='6ezo' size='340' side='right' viewer='molstar' caption='[[6ezo]], [[Resolution|resolution]] 4.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ezo]] is a 10 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human], [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EZO OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6EZO FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C7B:2-(4-chloranylphenoxy)-~{N}-[4-[2-(4-chloranylphenoxy)ethanoylamino]cyclohexyl]ethanamide'>C7B</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5b04|5b04]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EIF2B2, EIF2BB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ezo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ezo OCA], [http://pdbe.org/6ezo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ezo RCSB], [http://www.ebi.ac.uk/pdbsum/6ezo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ezo ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/EI2BD_HUMAN EI2BD_HUMAN]] Juvenile or adult CACH syndrome;Congenital or early infantile CACH syndrome;Cree leukoencephalopathy;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry. [[http://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. [[http://www.uniprot.org/uniprot/EI2BG_HUMAN EI2BG_HUMAN]] Juvenile or adult CACH syndrome;Congenital or early infantile CACH syndrome;Cree leukoencephalopathy;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry. [[http://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. [[http://www.uniprot.org/uniprot/EI2BE_HUMAN EI2BE_HUMAN]] Defects in EIF2B5 are a cause of leukodystrophy with vanishing white matter (VWM) [MIM:[http://omim.org/entry/603896 603896]]. VWM is a leukodystrophy that occurs mainly in children. Neurological signs include progressive cerebellar ataxia, spasticity, inconstant optic atrophy and relatively preserved mental abilities. The disease is chronic-progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. While childhood onset is the most common form of the disorder, some severe forms are apparent at birth. A severe, early-onset form seen among the Cree and Chippewayan populations of Quebec and Manitoba is called Cree leukoencephalopathy. Milder forms may not become evident until adolescence or adulthood. Some females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.<ref>PMID:11704758</ref> <ref>PMID:12325082</ref> <ref>PMID:12707859</ref> <ref>PMID:15776425</ref> <ref>PMID:19158808</ref> <ref>PMID:21484434</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/EI2BD_HUMAN EI2BD_HUMAN]] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. [[http://www.uniprot.org/uniprot/EI2BA_HUMAN EI2BA_HUMAN]] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. [[http://www.uniprot.org/uniprot/EI2BG_HUMAN EI2BG_HUMAN]] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. [[http://www.uniprot.org/uniprot/EI2BB_HUMAN EI2BB_HUMAN]] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. [[http://www.uniprot.org/uniprot/EI2BE_HUMAN EI2BE_HUMAN]] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. 
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== Publication Abstract from PubMed ==
The integrated stress response (ISR) is a conserved translational and transcriptional program affecting metabolism, memory, and immunity. The ISR is mediated by stress-induced phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, reverses the attenuation of eIF2B by phosphorylated eIF2alpha, protecting mice from neurodegeneration and traumatic brain injury. We describe a 4.1-angstrom-resolution cryo-electron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the beta and delta regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchical cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. Our findings point to a site in eIF2B that can be exploited by ISRIB to regulate translation.

Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.,Zyryanova AF, Weis F, Faille A, Alard AA, Crespillo-Casado A, Sekine Y, Harding HP, Allen F, Parts L, Fromont C, Fischer PM, Warren AJ, Ron D Science. 2018 Mar 30;359(6383):1533-1536. doi: 10.1126/science.aar5129. PMID:29599245<ref>PMID:29599245</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ezo" style="background-color:#fffaf0;"></div>

==See Also==
*[[Eukaryotic initiation factor 3D structures|Eukaryotic initiation factor 3D structures]]
== References ==
<references/>
__TOC__
</SX>
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Faille, A]]
[[Category: Ron, D]]
[[Category: Warren, A J]]
[[Category: Weis, F]]
[[Category: Zyryanova, A]]
[[Category: Complex]]
[[Category: Gef]]
[[Category: Isrib]]
[[Category: Membrane protein]]