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| | ==Crystal Structure of eIF4E in Complex with a Stapled Peptide Derivative== | | ==Crystal Structure of eIF4E in Complex with a Stapled Peptide Derivative== |
| - | <StructureSection load='4bea' size='340' side='right' caption='[[4bea]], [[Resolution|resolution]] 2.57Å' scene=''> | + | <StructureSection load='4bea' size='340' side='right'caption='[[4bea]], [[Resolution|resolution]] 2.57Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4bea]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BEA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BEA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4bea]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BEA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BEA FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NME:METHYLAMINE'>NME</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.57Å</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=4bea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bea OCA], [http://pdbe.org/4bea PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bea RCSB], [http://www.ebi.ac.uk/pdbsum/4bea PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bea ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=4bea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bea OCA], [https://pdbe.org/4bea PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bea RCSB], [https://www.ebi.ac.uk/pdbsum/4bea PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bea ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Eukaryotic initiation factor|Eukaryotic initiation factor]] | + | *[[Eukaryotic initiation factor 3D structures|Eukaryotic initiation factor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Brown, C J]] | + | [[Category: Large Structures]] |
| - | [[Category: Lama, D]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Lane, D P]] | + | [[Category: Brown CJ]] |
| - | [[Category: Quah, S T]] | + | [[Category: Lama D]] |
| - | [[Category: Verma, C S]] | + | [[Category: Lane DP]] |
| - | [[Category: Translation]] | + | [[Category: Quah ST]] |
| | + | [[Category: Verma CS]] |
| Structural highlights
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
eIF4E is frequently over-expressed in different cancers and causes increased translation of oncogenic proteins via deregulated cap-dependent translation. Inhibitors of the eIF4E:eIF4G interactions represent an approach that would normalize cap-dependent translation. Stapled peptides represent an emerging class of therapeutics that can target protein: protein interactions. We present here molecular dynamics simulations for a set of rationally designed stapled peptides in solution and in complex with eIF4E, supported with biophysical and crystallographic data. Clustering of the simulated structures revealed the favoured conformational states of the stapled peptides in their bound or free forms in solution. Identifying these populations has allowed us to design peptides with improved affinities by introducing mutations into the peptide sequence to alter their conformational distributions. These studies emphasise the effects that engineered mutations have on the conformations of free and bound peptides, and illustrate that both states must be considered in efforts to attain high affinity binding.
Rational Optimization of Conformational Effects Induced By Hydrocarbon Staples in Peptides and their Binding Interfaces.,Lama D, Quah ST, Verma CS, Lakshminarayanan R, Beuerman RW, Lane DP, Brown CJ Sci Rep. 2013 Dec 13;3:3451. doi: 10.1038/srep03451. PMID:24336354[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Lama D, Quah ST, Verma CS, Lakshminarayanan R, Beuerman RW, Lane DP, Brown CJ. Rational Optimization of Conformational Effects Induced By Hydrocarbon Staples in Peptides and their Binding Interfaces. Sci Rep. 2013 Dec 13;3:3451. doi: 10.1038/srep03451. PMID:24336354 doi:http://dx.doi.org/10.1038/srep03451
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