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4tpw

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Revision as of 11:13, 11 August 2016

The co-complex structure of the translation initiation factor eIF4E with the inhibitor 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G

Structural highlights

4tpw is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tomoo K, Matsushita Y, Fujisaki H, Abiko F, Shen X, Taniguchi T, Miyagawa H, Kitamura K, Miura K, Ishida T. Structural basis for mRNA Cap-Binding regulation of eukaryotic initiation factor 4E by 4E-binding protein, studied by spectroscopic, X-ray crystal structural, and molecular dynamics simulation methods. Biochim Biophys Acta. 2005 Dec 1;1753(2):191-208. Epub 2005 Aug 24. PMID:16271312 doi:10.1016/j.bbapap.2005.07.023
↑ 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. Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G. 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 doi:http://dx.doi.org/10.1073/pnas.1410250111

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4tpw"

@@ Line 1: / Line 1: @@
 ==The co-complex structure of the translation initiation factor eIF4E with the inhibitor 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G==
 <StructureSection load='4tpw' size='340' side='right' caption='[[4tpw]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
@@ Line 4: / Line 5: @@
 <table><tr><td colspan='2'>[[4tpw]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TPW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TPW FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=33R:(2E)-2-{2-[4-(3,4-DICHLOROPHENYL)-1,3-THIAZOL-2-YL]HYDRAZINYLIDENE}-3-(2-NITROPHENYL)PROPANOIC+ACID'>33R</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MGP:7-METHYL-GUANOSINE-5-TRIPHOSPHATE'>MGP</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4tpw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tpw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4tpw RCSB], [http://www.ebi.ac.uk/pdbsum/4tpw PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4tpw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tpw OCA], [http://pdbe.org/4tpw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tpw RCSB], [http://www.ebi.ac.uk/pdbsum/4tpw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4tpw ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 16: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4tpw" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Eukaryotic initiation factor|Eukaryotic initiation factor]]
 == References ==
 <references/>

4tpw

From Proteopedia

Revision as of 11:13, 11 August 2016

The co-complex structure of the translation initiation factor eIF4E with the inhibitor 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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