Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G

The interaction of the eukaryotic translation initiation factor eIF4E with the initiation factor eIF4G recruits the 40S ribosomal particle to the 5′ end of mRNAs, facilitates scanning to the AUG start codon, and is crucial for eukaryotic translation of nearly all genes. Efficient recruitment of the...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2014-08, Vol.111 (31), p.E3187-E3195
Main Authors: Papadopoulos, Evangelos, Jenni, Simon, Kabha, Eihab, Takrouri, Khuloud J, Yi, Tingfang, Salvi, Nicola, Luna, Rafael E, Gavathiotis, Evripidis, Mahalingam, Poornachandran, Arthanari, Haribabu, Rodriguez-Mias, Ricard, Yefidoff-Freedman, Revital, Aktas, Bertal H, Chorev, Michael, Halperin, Jose A, Wagner, Gerhard
Format: Article
Language:English
Subjects:
Allosteric Regulation
Binding Sites
Biological Sciences
Cancer
Crystal structure
Crystallography, X-Ray
Eukaryotes
Eukaryotic Initiation Factor-4E - antagonists & inhibitors
Eukaryotic Initiation Factor-4E - chemistry
Eukaryotic Initiation Factor-4E - metabolism
Eukaryotic Initiation Factor-4G - chemistry
Eukaryotic Initiation Factor-4G - metabolism
Genes
Humans
Hydrazones - chemistry
Hydrazones - metabolism
Ligands
Magnetic Resonance Spectroscopy
Models, Molecular
Mutagenesis, Site-Directed
NMR
Nuclear magnetic resonance
Peptides - chemistry
Peptides - metabolism
PNAS Plus
Protein Structure, Quaternary
Protein Structure, Secondary
Ribonucleic acid
RNA
RNA Caps - metabolism
Solutions
Thiazoles - chemistry
Thiazoles - metabolism
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Summary:The interaction of the eukaryotic translation initiation factor eIF4E with the initiation factor eIF4G recruits the 40S ribosomal particle to the 5′ end of mRNAs, facilitates scanning to the AUG start codon, and is crucial for eukaryotic translation of nearly all genes. Efficient recruitment of the 40S particle is particularly important for translation of mRNAs encoding oncoproteins and growth-promoting factors, which often harbor complex 5′ UTRs and require efficient initiation. Thus, inhibiting the eIF4E/eIF4G interaction has emerged as a previously unpursued route for developing anticancer agents. Indeed, we discovered small-molecule inhibitors of this eIF4E/eIF4G interaction (4EGIs) that inhibit translation initiation both in vitro and in vivo and were used successfully in numerous cancer–biology and neurobiology studies. However, their detailed molecular mechanism of action has remained elusive. Here, we show that the eIF4E/eIF4G inhibitor 4EGI-1 acts allosterically by binding to a site on eIF4E distant from the eIF4G binding epitope. Data from NMR mapping and high-resolution crystal structures are congruent with this mechanism, where 4EGI-1 attaches to a hydrophobic pocket of eIF4E between β-sheet ₂ (L ₆₀-T ₆₈) and α-helix ₁ (E ₆₉-N ₇₇), causing localized conformational changes mainly in the H ₇₈-L ₈₅ region. It acts by unfolding a short 3 ₁₀-helix (S ₈₂-L ₈₅) while extending α-helix ₁ by one turn (H ₇₈-S ₈₂). This unusual helix rearrangement has not been seen in any previous eIF4E structure and reveals elements of an allosteric inhibition mechanism leading to the dislocation of eIF4G from eIF4E.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1410250111