1l8b
From Proteopedia
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| - | + | {{STRUCTURE_1l8b| PDB=1l8b | SCENE= }} | |
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'''Cocrystal Structure of the Messenger RNA 5' Cap-binding Protein (eIF4E) bound to 7-methylGpppG''' | '''Cocrystal Structure of the Messenger RNA 5' Cap-binding Protein (eIF4E) bound to 7-methylGpppG''' | ||
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[[Category: Wyslouch-Cieszynska, A.]] | [[Category: Wyslouch-Cieszynska, A.]] | ||
[[Category: 7-methylgpppg]] | [[Category: 7-methylgpppg]] | ||
| - | [[Category: | + | [[Category: Cap]] |
| - | [[Category: | + | [[Category: Eif4e]] |
| - | [[Category: | + | [[Category: Eukaryotic initiation factor 4e]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 23:39:28 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 20:39, 2 May 2008
Cocrystal Structure of the Messenger RNA 5' Cap-binding Protein (eIF4E) bound to 7-methylGpppG
Overview
mRNA 5'-cap recognition by the eukaryotic translation initiation factor eIF4E has been exhaustively characterized with the aid of a novel fluorometric, time-synchronized titration method, and X-ray crystallography. The association constant values of recombinant eIF4E for 20 different cap analogues cover six orders of magnitude; with the highest affinity observed for m(7)GTP (approximately 1.1 x 10(8) M(-1)). The affinity of the cap analogues for eIF4E correlates with their ability to inhibit in vitro translation. The association constants yield contributions of non-covalent interactions involving single structural elements of the cap to the free energy of binding, giving a reliable starting point to rational drug design. The free energy of 7-methylguanine stacking and hydrogen bonding (-4.9 kcal/mol) is separate from the energies of phosphate chain interactions (-3.0, -1.9, -0.9 kcal/mol for alpha, beta, gamma phosphates, respectively), supporting two-step mechanism of the binding. The negatively charged phosphate groups of the cap act as a molecular anchor, enabling further formation of the intermolecular contacts within the cap-binding slot. Stabilization of the stacked Trp102/m(7)G/Trp56 configuration is a precondition to form three hydrogen bonds with Glu103 and Trp102. Electrostatically steered eIF4E-cap association is accompanied by additional hydration of the complex by approximately 65 water molecules, and by ionic equilibria shift. Temperature dependence reveals the enthalpy-driven and entropy-opposed character of the m(7)GTP-eIF4E binding, which results from dominant charge-related interactions (DeltaH degrees =-17.8 kcal/mol, DeltaS degrees= -23.6 cal/mol K). For recruitment of synthetic eIF4GI, eIF4GII, and 4E-BP1 peptides to eIF4E, all the association constants were approximately 10(7) M(-1), in decreasing order: eIF4GI>4E-BP1>eIF4GII approximately 4E-BP1(P-Ser65) approximately 4E-BP1(P-Ser65/Thr70). Phosphorylation of 4E-BP1 at Ser65 and Thr70 is insufficient to prevent binding to eIF4E. Enhancement of the eIF4E affinity for cap occurs after binding to eIF4G peptides.
About this Structure
1L8B is a Single protein structure of sequence from Mus musculus. Full crystallographic information is available from OCA.
Reference
Biophysical studies of eIF4E cap-binding protein: recognition of mRNA 5' cap structure and synthetic fragments of eIF4G and 4E-BP1 proteins., Niedzwiecka A, Marcotrigiano J, Stepinski J, Jankowska-Anyszka M, Wyslouch-Cieszynska A, Dadlez M, Gingras AC, Mak P, Darzynkiewicz E, Sonenberg N, Burley SK, Stolarski R, J Mol Biol. 2002 Jun 7;319(3):615-35. PMID:12054859 Page seeded by OCA on Fri May 2 23:39:28 2008
