title: Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G.
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.
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors: Evangelos
authors: E
authors: Papadopoulos
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors: Simon
authors: S
authors: Jenni
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;Laboratory for Translational Research, Harvard Medical School, Cambridge, MA 02139;
authors: Eihab
authors: E
authors: Kabha
authors: Laboratory for Translational Research, Harvard Medical School, Cambridge, MA 02139;Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors: Khuloud J
authors: KJ
authors: Takrouri
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors: Tingfang
authors: T
authors: Yi
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors: Nicola
authors: N
authors: Salvi
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors: Rafael E
authors: RE
authors: Luna
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;Jack and Pearl Resnick Campus, Albert Einstein College of Medicine, Bronx, NY 10461; and.
authors: Evripidis
authors: E
authors: Gavathiotis
authors: Laboratory for Translational Research, Harvard Medical School, Cambridge, MA 02139;Rowland Institute, Harvard University, Cambridge, MA 02142.
authors: Poornachandran
authors: P
authors: Mahalingam
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors: Haribabu
authors: H
authors: Arthanari
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors: Ricard
authors: R
authors: Rodriguez-Mias
authors: Laboratory for Translational Research, Harvard Medical School, Cambridge, MA 02139;Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors: Revital
authors: R
authors: Yefidoff-Freedman
authors: Laboratory for Translational Research, Harvard Medical School, Cambridge, MA 02139;
authors: Bertal H
authors: BH
authors: Aktas
authors: Laboratory for Translational Research, Harvard Medical School, Cambridge, MA 02139;
authors: Michael
authors: M
authors: Chorev
authors: Laboratory for Translational Research, Harvard Medical School, Cambridge, MA 02139;
authors: Jose A
authors: JA
authors: Halperin
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; gerhard_wagner@hms.harvard.edu.
authors: Gerhard
authors: G
authors: Wagner
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D018360:Crystallography, X-Ray; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012315:RNA Caps / Q000378:metabolism; D012996:Solutions; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C517852:4EGI-1 compound; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D006835:Hydrazones; D008024:Ligands; D010455:Peptides; D012315:RNA Caps; D012996:Solutions; D013844:Thiazoles
keywords: NMR spectroscopy; allosteric inhibitor; inhibitor of protein–protein interaction