View source for 4tqc


==The co-complex structure of the translation initiation factor eIF4E with the inhibitor 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G==
<StructureSection load='4tqc' size='340' side='right'caption='[[4tqc]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4tqc]] 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=4TQC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TQC 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=34J:(2S)-3-(4-AMINO-3-NITROPHENYL)-2-{2-[4-(3,4-DICHLOROPHENYL)-1,3-THIAZOL-2-YL]HYDRAZINYL}PROPANOIC+ACID'>34J</scene>, <scene name='pdbligand=M7G:7N-METHYL-8-HYDROGUANOSINE-5-DIPHOSPHATE'>M7G</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=4tqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tqc OCA], [https://pdbe.org/4tqc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tqc RCSB], [https://www.ebi.ac.uk/pdbsum/4tqc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tqc ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/IF4E_HUMAN IF4E_HUMAN] Its translation stimulation activity is repressed by binding to the complex CYFIP1-FMR1 (By similarity). Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates the binding to the mRNA cap.<ref>PMID:16271312</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The interaction of the eukaryotic translation initiation factor eIF4E with the initiation factor eIF4G recruits the 40S ribosomal particle to the 5' end of mRNAs, facilitates scanning to the AUG start codon, and is crucial for eukaryotic translation of nearly all genes. Efficient recruitment of the 40S particle is particularly important for translation of mRNAs encoding oncoproteins and growth-promoting factors, which often harbor complex 5' UTRs and require efficient initiation. Thus, inhibiting the eIF4E/eIF4G interaction has emerged as a previously unpursued route for developing anticancer agents. Indeed, we discovered small-molecule inhibitors of this eIF4E/eIF4G interaction (4EGIs) that inhibit translation initiation both in vitro and in vivo and were used successfully in numerous cancer-biology and neurobiology studies. However, their detailed molecular mechanism of action has remained elusive. Here, we show that the eIF4E/eIF4G inhibitor 4EGI-1 acts allosterically by binding to a site on eIF4E distant from the eIF4G binding epitope. Data from NMR mapping and high-resolution crystal structures are congruent with this mechanism, where 4EGI-1 attaches to a hydrophobic pocket of eIF4E between beta-sheet2 (L60-T68) and alpha-helix1 (E69-N77), causing localized conformational changes mainly in the H78-L85 region. It acts by unfolding a short 310-helix (S82-L85) while extending alpha-helix1 by one turn (H78-S82). This unusual helix rearrangement has not been seen in any previous eIF4E structure and reveals elements of an allosteric inhibition mechanism leading to the dislocation of eIF4G from eIF4E.

Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G.,Papadopoulos E, Jenni S, Kabha E, Takrouri KJ, Yi T, Salvi N, Luna RE, Gavathiotis E, Mahalingam P, Arthanari H, Rodriguez-Mias R, Yefidoff-Freedman R, Aktas BH, Chorev M, Halperin JA, Wagner G Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):E3187-95. doi:, 10.1073/pnas.1410250111. Epub 2014 Jul 21. PMID:25049413<ref>PMID:25049413</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4tqc" style="background-color:#fffaf0;"></div>

==See Also==
*[[Eukaryotic initiation factor 3D structures|Eukaryotic initiation factor 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Jenni S]]
[[Category: Papadopoulos E]]
[[Category: Wagner G]]