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| | <StructureSection load='5j5y' size='340' side='right'caption='[[5j5y]], [[Resolution|resolution]] 1.75Å' scene=''> | | <StructureSection load='5j5y' size='340' side='right'caption='[[5j5y]], [[Resolution|resolution]] 1.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5j5y]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J5Y OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5J5Y FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5j5y]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J5Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J5Y FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6G6:2-AMINO-9-{5-O-[(R)-{[(S)-{DICHLORO[(R)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]METHYL}(HYDROXY)PHOSPHORYL]OXY}(HYDROXY)PHOSPHORYL]-2-O-METHYL-BETA-D-RIBOFURANOSYL}-7-METHYL-9H-PURIN-7-IUM-6-OLATE'>6G6</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 1.75Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Eif4e ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6G6:2-AMINO-9-{5-O-[(R)-{[(S)-{DICHLORO[(R)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]METHYL}(HYDROXY)PHOSPHORYL]OXY}(HYDROXY)PHOSPHORYL]-2-O-METHYL-BETA-D-RIBOFURANOSYL}-7-METHYL-9H-PURIN-7-IUM-6-OLATE'>6G6</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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=5j5y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j5y OCA], [http://pdbe.org/5j5y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j5y RCSB], [http://www.ebi.ac.uk/pdbsum/5j5y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j5y ProSAT]</span></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=5j5y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j5y OCA], [https://pdbe.org/5j5y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j5y RCSB], [https://www.ebi.ac.uk/pdbsum/5j5y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j5y ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/IF4E_MOUSE IF4E_MOUSE]] 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. May play an important role in spermatogenesis through translational regulation of stage-specific mRNAs during germ cell development (By similarity). Its translation stimulation activity is repressed by binding to the complex CYFIP1-FMR1. 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:18805096</ref> | + | [https://www.uniprot.org/uniprot/IF4E_MOUSE IF4E_MOUSE] 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. May play an important role in spermatogenesis through translational regulation of stage-specific mRNAs during germ cell development (By similarity). Its translation stimulation activity is repressed by binding to the complex CYFIP1-FMR1. 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:18805096</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Jemielity, J]] | + | [[Category: Jemielity J]] |
| - | [[Category: Kowalska, J]] | + | [[Category: Kowalska J]] |
| - | [[Category: Nowak, E]] | + | [[Category: Nowak E]] |
| - | [[Category: Nowotny, M]] | + | [[Category: Nowotny M]] |
| - | [[Category: Rydzik, A M]] | + | [[Category: Rydzik AM]] |
| - | [[Category: Warminski, M]] | + | [[Category: Warminski M]] |
| - | [[Category: Dichloromethylenebisphosphonate]]
| + | |
| - | [[Category: Eif4e]]
| + | |
| - | [[Category: Mrna 5' cap analog]]
| + | |
| - | [[Category: Protein-ligand complex]]
| + | |
| - | [[Category: Translation]]
| + | |
| - | [[Category: Translation initiation factor]]
| + | |
| Structural highlights
Function
IF4E_MOUSE 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. May play an important role in spermatogenesis through translational regulation of stage-specific mRNAs during germ cell development (By similarity). Its translation stimulation activity is repressed by binding to the complex CYFIP1-FMR1. 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
Analogues of the mRNA 5'-cap are useful tools for studying mRNA translation and degradation, with emerging potential applications in novel therapeutic interventions including gene therapy. We report the synthesis of novel mono- and dinucleotide cap analogues containing dihalogenmethylenebisphosphonate moiety (i.e. one of the bridging O atom substituted with CCl2 or CF2) and their properties in the context of cellular translational and decapping machineries, compared to phosphate-unmodified and previously reported CH2-substituted caps. The analogues were bound tightly to eukaryotic translation initiation factor 4E (eIF4E), with CCl2-substituted analogues having the highest affinity. When incorporated into mRNA, the CCl2-substituted dinucleotide most efficiently promoted cap-dependent translation. Moreover, the CCl2-analogues were potent inhibitors of translation in rabbit reticulocyte lysate. The crystal structure of eIF4E in complex with the CCl2-analogue revealed a significantly different ligand conformation compared to that of the unmodified cap analogue, which likely contributes to the improved binding. Both CCl2- and CF2- analogues showed lower susceptibility to hydrolysis by the decapping scavenger enzyme (DcpS) and, when incorporated into RNA, conferred stability against major cellular decapping enzyme (Dcp2) to transcripts. Furthermore, the use of difluoromethylene cap analogues was exemplified by the development of 19F NMR assays for DcpS activity and eIF4E binding.
mRNA cap analogues substituted in the tetraphosphate chain with CX2: identification of O-to-CCl2 as the first bridging modification that confers resistance to decapping without impairing translation.,Rydzik AM, Warminski M, Sikorski PJ, Baranowski MR, Walczak S, Kowalska J, Zuberek J, Lukaszewicz M, Nowak E, W Claridge TD, Darzynkiewicz E, Nowotny M, Jemielity J Nucleic Acids Res. 2017 Sep 6;45(15):8661-8675. doi: 10.1093/nar/gkx569. PMID:28666355[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, Witke W, Costa-Mattioli M, Sonenberg N, Achsel T, Bagni C. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell. 2008 Sep 19;134(6):1042-54. doi: 10.1016/j.cell.2008.07.031. PMID:18805096 doi:http://dx.doi.org/10.1016/j.cell.2008.07.031
- ↑ Rydzik AM, Warminski M, Sikorski PJ, Baranowski MR, Walczak S, Kowalska J, Zuberek J, Lukaszewicz M, Nowak E, W Claridge TD, Darzynkiewicz E, Nowotny M, Jemielity J. mRNA cap analogues substituted in the tetraphosphate chain with CX2: identification of O-to-CCl2 as the first bridging modification that confers resistance to decapping without impairing translation. Nucleic Acids Res. 2017 Sep 6;45(15):8661-8675. doi: 10.1093/nar/gkx569. PMID:28666355 doi:http://dx.doi.org/10.1093/nar/gkx569
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