5ehc: Difference between revisions

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 ==Co-crystal structure of eIF4E with nucleotide mimetic inhibitor.==
-<StructureSection load='5ehc' size='340' side='right' caption='[[5ehc]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+<StructureSection load='5ehc' size='340' side='right'caption='[[5ehc]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ehc]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EHC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EHC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ehc]] is a 2 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=5EHC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EHC FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5NX:3-[[(2~{R},3~{S},4~{R},5~{R})-5-[2-AZANYL-7-[(3-CHLOROPHENYL)METHYL]-6-OXIDANYLIDENE-1~{H}-PURIN-7-IUM-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHYLAMINO]-4-OXIDANYL-CYCLOBUT-3-ENE-1,2-DIONE'>5NX</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]] 2.4&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2v8w|2v8w]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5NX:3-[[(2~{R},3~{S},4~{R},5~{R})-5-[2-AZANYL-7-[(3-CHLOROPHENYL)METHYL]-6-OXIDANYLIDENE-1~{H}-PURIN-7-IUM-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHYLAMINO]-4-OXIDANYL-CYCLOBUT-3-ENE-1,2-DIONE'>5NX</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=5ehc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ehc OCA], [http://pdbe.org/5ehc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ehc RCSB], [http://www.ebi.ac.uk/pdbsum/5ehc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ehc 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=5ehc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ehc OCA], [https://pdbe.org/5ehc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ehc RCSB], [https://www.ebi.ac.uk/pdbsum/5ehc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ehc ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[http://www.uniprot.org/uniprot/IF4G1_HUMAN IF4G1_HUMAN]] Defects in EIF4G1 are the cause of Parkinson disease type 18 (PARK18) [MIM:[http://omim.org/entry/614251 614251]]. An autosomal dominant, late-onset form of Parkinson disease. Parkinson disease is a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain.<ref>PMID:21907011</ref>
 == 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>  [[http://www.uniprot.org/uniprot/IF4G1_HUMAN IF4G1_HUMAN]] Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome.
+[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;">
+== 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<ref>PMID:27592390</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 5ehc" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Eukaryotic initiation factor 3D structures|Eukaryotic initiation factor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Fischer, P M]]
+[[Category: Homo sapiens]]
-[[Category: Nowicki, M W]]
+[[Category: Large Structures]]
-[[Category: Walkinshaw, M D]]
+[[Category: Fischer PM]]
-[[Category: Complex]]
+[[Category: Nowicki MW]]
-[[Category: Eif4e]]
+[[Category: Walkinshaw MD]]
-[[Category: Inhibitor]]
-[[Category: Translation]]