|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Co-crystal structure of eIF4E with inhibitor== | | ==Co-crystal structure of eIF4E with inhibitor== |
| - | <StructureSection load='4dum' size='340' side='right' caption='[[4dum]], [[Resolution|resolution]] 2.95Å' scene=''> | + | <StructureSection load='4dum' size='340' side='right'caption='[[4dum]], [[Resolution|resolution]] 2.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4dum]] is a 1 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=4DUM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DUM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4dum]] is a 1 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=4DUM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DUM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HLI:(4-{7-[2-(4-CHLOROPHENOXY)ETHYL]-2-(METHYLAMINO)-6-OXO-6,7-DIHYDRO-1H-PURIN-8-YL}PHENYL)PHOSPHONIC+ACID'>HLI</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HLI:(4-{7-[2-(4-CHLOROPHENOXY)ETHYL]-2-(METHYLAMINO)-6-OXO-6,7-DIHYDRO-1H-PURIN-8-YL}PHENYL)PHOSPHONIC+ACID'>HLI</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4dt6|4dt6]]</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=4dum FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dum OCA], [https://pdbe.org/4dum PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dum RCSB], [https://www.ebi.ac.uk/pdbsum/4dum PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dum ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EIF4E, EIF4EL1, EIF4F ([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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dum FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dum OCA], [http://pdbe.org/4dum PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dum RCSB], [http://www.ebi.ac.uk/pdbsum/4dum PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dum 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 == |
| Line 22: |
Line 20: |
| | | | |
| | ==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: Johnstone, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Min, X]] | + | [[Category: Johnstone S]] |
| - | [[Category: Walker, N]] | + | [[Category: Min X]] |
| - | [[Category: Wang, Z]] | + | [[Category: Walker N]] |
| - | [[Category: Cap-binding protein]]
| + | [[Category: Wang Z]] |
| - | [[Category: M7gtp]]
| + | |
| - | [[Category: Translation]]
| + | |
| - | [[Category: Translation initiation factor]]
| + | |
| 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
Abstract The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC50 of 2.5 M for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point towards the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.
Structure-guided design, synthesis and evaluation of guanine-derived inhibitors of the eIF4E mRNA-cap interaction.,Chen X, Kopecky D, Mihalic J, Jeffries S, Min X, Heath J, Deignan J, Sujen L, Fu Z, Guimaraes C, Li S, Johnstone S, Xu H, Cardozo M, Shen W, Walker N, Kayser F, Wang Z J Med Chem. 2012 Mar 29. PMID:22458568[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
- ↑ Chen X, Kopecky D, Mihalic J, Jeffries S, Min X, Heath J, Deignan J, Sujen L, Fu Z, Guimaraes C, Li S, Johnstone S, Xu H, Cardozo M, Shen W, Walker N, Kayser F, Wang Z. Structure-guided design, synthesis and evaluation of guanine-derived inhibitors of the eIF4E mRNA-cap interaction. J Med Chem. 2012 Mar 29. PMID:22458568 doi:10.1021/jm300037x
|
