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

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

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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-sheet2 (L60-T68) and α-helix1 (E69-N77), causing localized conformational changes mainly in the H78-L85 region. It acts by unfolding a short 310-helix (S82-L85) while extending α-helix1 by one turn (H78-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.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number31
DOIs
StatePublished - Aug 5 2014

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Eukaryotic Initiation Factors
Peptide Initiation Factors
Initiator Codon
Neurobiology
5' Untranslated Regions
Oncogene Proteins
Protein Biosynthesis
Antineoplastic Agents
Epitopes
Intercellular Signaling Peptides and Proteins
Messenger RNA
Genes
Neoplasms
In Vitro Techniques

Keywords

  • Allosteric inhibitor
  • Inhibitor of protein-protein interaction
  • NMR spectroscopy

ASJC Scopus subject areas

  • General

Cite this

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 31, 05.08.2014.

Research output: Contribution to journalArticle

Papadopoulos, E, Jenni, S, Kabha, E, Takrouri, KJ, Yi, T, Salvi, N, Luna, RE, Gavathiotis, E, Mahalingam, P, Arthanari, H, Rodriguez-Mias, R, Yefidoff-Freedman, R, Aktas, BH, Chorev, M, Halperin, JA & Wagner, G 2014, 'Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 31. https://doi.org/10.1073/pnas.1410250111
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. / Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 31.
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AU - Jenni, Simon

AU - Kabha, Eihab

AU - Takrouri, Khuloud J.

AU - Yi, Tingfang

AU - Salvi, Nicola

AU - Luna, Rafael E.

AU - Gavathiotis, Evripidis

AU - Mahalingam, Poornachandran

AU - Arthanari, Haribabu

AU - Rodriguez-Mias, Ricard

AU - Yefidoff-Freedman, Revital

AU - Aktas, Bertal H.

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AU - Halperin, Jose A.

AU - Wagner, Gerhard

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