|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Co-crystal structure of eIF4E with nucleotide mimetic inhibitor.== | | ==Co-crystal structure of eIF4E with nucleotide mimetic inhibitor.== |
| - | <StructureSection load='5ei3' size='340' side='right' caption='[[5ei3]], [[Resolution|resolution]] 1.71Å' scene=''> | + | <StructureSection load='5ei3' size='340' side='right'caption='[[5ei3]], [[Resolution|resolution]] 1.71Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ei3]] 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=5EI3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EI3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ei3]] 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=5EI3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EI3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5O8:~{N}-[[(2~{R},3~{S},4~{R},5~{R})-5-[2-AZANYL-6-OXIDANYLIDENE-7-(PHENYLMETHYL)-1~{H}-PURIN-7-IUM-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHYL]-1,1,1-TRIS(FLUORANYL)METHANESULFONAMIDE'>5O8</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.71Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2v8w|2v8w]], [[5ehc|5ehc]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5O8:~{N}-[[(2~{R},3~{S},4~{R},5~{R})-5-[2-AZANYL-6-OXIDANYLIDENE-7-(PHENYLMETHYL)-1~{H}-PURIN-7-IUM-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHYL]-1,1,1-TRIS(FLUORANYL)METHANESULFONAMIDE'>5O8</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5ei3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ei3 OCA], [https://pdbe.org/5ei3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ei3 RCSB], [https://www.ebi.ac.uk/pdbsum/5ei3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ei3 ProSAT]</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=5ei3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ei3 OCA], [http://pdbe.org/5ei3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ei3 RCSB], [http://www.ebi.ac.uk/pdbsum/5ei3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ei3 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 20: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 5ei3" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5ei3" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Eukaryotic initiation factor 3D structures|Eukaryotic initiation factor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Fischer, P M]] | + | [[Category: Large Structures]] |
| - | [[Category: Nowicki, M W]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Walkinshaw, M D]] | + | [[Category: Fischer PM]] |
| - | [[Category: Complex]] | + | [[Category: Nowicki MW]] |
| - | [[Category: Eif4e]] | + | [[Category: Walkinshaw MD]] |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Translation]]
| + | |
| 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
Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 5'-terminal mRNA cap structure (m7GpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design cap-binding inhibitors of eIF4E by modifying the N7-substituent of m7GMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N-[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5-g]quinolin-7-yl)methyl]-N'-(2-methyl-propyl )-N-(phenyl-methyl)thiourea (14), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified m7GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 5'-deoxy-5'-(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N7-methyl-guanosine (4a), N7-3-chlorobenzyl-5'-deoxy-5'-(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guano sine (4f), and N7-benzyl-5'-deoxy-5'-(trifluoromethyl-sulfamoyl)guanosine (7a). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents.
Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation.,Soukarieh F, Nowicki MW, Bastide A, Poyry T, Jones C, Dudek K, Patwardhan G, Meullenet F, Oldham NJ, Walkinshaw MD, Willis AE, Fischer PM Eur J Med Chem. 2016 Aug 24;124:200-217. doi: 10.1016/j.ejmech.2016.08.047. PMID:27592390[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
- ↑ Soukarieh F, Nowicki MW, Bastide A, Poyry T, Jones C, Dudek K, Patwardhan G, Meullenet F, Oldham NJ, Walkinshaw MD, Willis AE, Fischer PM. Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation. Eur J Med Chem. 2016 Aug 24;124:200-217. doi: 10.1016/j.ejmech.2016.08.047. PMID:27592390 doi:http://dx.doi.org/10.1016/j.ejmech.2016.08.047
|
