4TQC

The co-complex structure of the translation initiation factor eIF4E with the inhibitor 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G

4TQC の概要

• エントリーDOI: 10.2210/pdb4tqc/pdb
• 関連するPDBエントリー: 4TPW 4TQB
• 分子名称: Eukaryotic translation initiation factor 4E, 7N-METHYL-8-HYDROGUANOSINE-5'-DIPHOSPHATE, (2S)-3-(4-amino-3-nitrophenyl)-2-{2-[4-(3,4-dichlorophenyl)-1,3-thiazol-2-yl]hydrazinyl}propanoic acid, ... (4 entities in total)
• 機能のキーワード: eif4e, translation initiation inhibitor, allosteric, 4egi1, protein binding
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, P-body : P06730
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 45967.47

構造登録者

Papadopoulos, E.,Jenni, S.,Wagner, G. (登録日: 2014-06-10, 公開日: 2014-08-13, 最終更新日: 2023-12-27)

主引用文献

Papadopoulos, E.,Jenni, S.,Kabha, E.,Takrouri, K.J.,Yi, T.,Salvi, N.,Luna, R.E.,Gavathiotis, E.,Mahalingam, P.,Arthanari, H.,Rodriguez-Mias, R.,Yefidoff-Freedman, R.,Aktas, B.H.,Chorev, M.,Halperin, J.A.,Wagner, G.
Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G.
Proc.Natl.Acad.Sci.USA, 111:E3187-E3195, 2014

PubMed 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-S82). 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.

PubMed: 25049413
DOI: 10.1073/pnas.1410250111

実験手法

X-RAY DIFFRACTION (1.8 Å)