Journal Article

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

Gerhard Wagner, Evangelos Papadopoulos, Eihab Kabha, Jose A. Halperin, Tingfang Yi, Poornachandran Mahalingam, Simon Jenni, Ricard Rodriguez-Mias, Rafael E. Luna, Revital Yefidoff-Freedman, Michael Chorev, Nicola Salvi, Evripidis Gavathiotis, Khuloud J. Takrouri, Haribabu Arthanari, Bertal H. Aktas

2014

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Allosteric Regulation / antineoplastic agents / Binding Sites / Biological Sciences / Cancer / Crystal structure / Crystallography, X-Ray / epitopes / 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 / hydrophobicity / Ligands / Magnetic Resonance Spectroscopy / mechanism of action / messenger RNA / Models, Molecular / Mutagenesis, Site-Directed / neurophysiology / NMR / Nuclear magnetic resonance / nuclear magnetic resonance spectroscopy / oncogene proteins / Peptides - chemistry / Peptides - metabolism / PNAS Plus / Protein Structure, Quaternary / Protein Structure, Secondary / Ribonucleic acid / RNA / RNA Caps - metabolism / Solutions / start codon / Thiazoles - chemistry / Thiazoles - metabolism / translation (genetics)