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2v8w

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Revision as of 11:54, 25 December 2014

CRYSTALLOGRAPHIC AND MASS SPECTROMETRIC CHARACTERISATION OF EIF4E WITH N7-CAP DERIVATIVES

Structural highlights

2v8w is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1ipb, 1ipc, 2jgc, 2jgb, 2v8x, 2v8y
Resources:	FirstGlance, OCA, RCSB, PDBsum

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] [4EBP1_HUMAN] Regulates eIF4E activity by preventing its assembly into the eIF4F complex. Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways.^[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Structural complexes of the eukaryotic translation initiation factor 4E (eIF4E) with a series of N(7)-alkylated guanosine derivative mRNA cap analogue structures have been characterised. Mass spectrometry was used to determine apparent gas-phase equilibrium dissociation constants (K(d)) values of 0.15 microM, 13.6 microM, and 55.7 microM for eIF4E with 7-methyl-GTP (m(7)GTP), GTP, and GMP, respectively. For tight and specific binding to the eIF4E mononucleotide binding site, there seems to be a clear requirement for guanosine derivatives to possess both the delocalised positive charge of the N(7)-methylated guanine system and at least one phosphate group. We show that the N(7)-benzylated monophosphates 7-benzyl-GMP (Bn(7)GMP) and 7-(p-fluorobenzyl)-GMP (FBn(7)GMP) bind eIF4E substantially more tightly than non-N(7)-alkylated guanosine derivatives (K(d) values of 7.0 microM and 2.0 microM, respectively). The eIF4E complex crystal structures with Bn(7)GMP and FBn(7)GMP show that additional favourable contacts of the benzyl groups with eIF4E contribute binding energy that compensates for loss of the beta and gamma-phosphates. The N(7)-benzyl groups pack into a hydrophobic pocket behind the two tryptophan side-chains that are involved in the cation-pi stacking interaction between the cap and the eIF4E mononucleotide binding site. This pocket is formed by an induced fit in which one of the tryptophan residues involved in cap binding flips through 180 degrees relative to structures with N(7)-methylated cap derivatives. This and other observations made here will be useful in the design of new families of eIF4E inhibitors, which may have potential therapeutic applications in cancer.

Crystallographic and mass spectrometric characterisation of eIF4E with N7-alkylated cap derivatives.,Brown CJ, McNae I, Fischer PM, Walkinshaw MD J Mol Biol. 2007 Sep 7;372(1):7-15. Epub 2007 Jun 15. PMID:17631896^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Pause A, Belsham GJ, Gingras AC, Donze O, Lin TA, Lawrence JC Jr, Sonenberg N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature. 1994 Oct 27;371(6500):762-7. PMID:7935836 doi:http://dx.doi.org/10.1038/371762a0
↑ Brown CJ, McNae I, Fischer PM, Walkinshaw MD. Crystallographic and mass spectrometric characterisation of eIF4E with N7-alkylated cap derivatives. J Mol Biol. 2007 Sep 7;372(1):7-15. Epub 2007 Jun 15. PMID:17631896 doi:10.1016/j.jmb.2007.06.033

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2v8w"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[2v8w]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2V8W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2V8W FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MGO:[[(2R,3S,4R,5R)-5-(6-AMINO-3-METHYL-4-OXO-5H-IMIDAZO[4,5-C]PYRIDIN-1-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHOXY-HYDROXY-PHOSPHORYL]+PHOSPHONO+HYDROGEN+PHOSPHATE'>MGO</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MGO:[[(2R,3S,4R,5R)-5-(6-AMINO-3-METHYL-4-OXO-5H-IMIDAZO[4,5-C]PYRIDIN-1-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHOXY-HYDROXY-PHOSPHORYL]+PHOSPHONO+HYDROGEN+PHOSPHATE'>MGO</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ipb|1ipb]], [[1ipc|1ipc]], [[2jgc|2jgc]], [[2jgb|2jgb]], [[2v8x|2v8x]], [[2v8y|2v8y]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ipb|1ipb]], [[1ipc|1ipc]], [[2jgc|2jgc]], [[2jgb|2jgb]], [[2v8x|2v8x]], [[2v8y|2v8y]]</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2v8w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v8w OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2v8w RCSB], [http://www.ebi.ac.uk/pdbsum/2v8w PDBsum]</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=2v8w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v8w OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2v8w RCSB], [http://www.ebi.ac.uk/pdbsum/2v8w PDBsum]</span></td></tr>
-<table>
+</table>
+== 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/4EBP1_HUMAN 4EBP1_HUMAN]] Regulates eIF4E activity by preventing its assembly into the eIF4F complex. Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways.<ref>PMID:7935836</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 33: / Line 35: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Brown, C J.]]
+[[Category: Brown, C J]]
-[[Category: Fischer, P M.]]
+[[Category: Fischer, P M]]
-[[Category: Mcnae, I.]]
+[[Category: Mcnae, I]]
-[[Category: Walkinshaw, M D.]]
+[[Category: Walkinshaw, M D]]
 [[Category: 4e-bp1]]
 [[Category: Cap]]

2v8w

From Proteopedia

Revision as of 11:54, 25 December 2014

CRYSTALLOGRAPHIC AND MASS SPECTROMETRIC CHARACTERISATION OF EIF4E WITH N7-CAP DERIVATIVES

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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