PDBsum entry 4tqc

Protein binding

PDB id: 4tqc

Contents

Protein chains

176 a.a.

Ligands

M7G ×2

34J

Waters ×410

PDB id:

4tqc

Name:

Protein binding

Title:

The co-complex structure of the translation initiation factor eif4e with the inhibitor 4egi-1 reveals an allosteric mechanism for dissociating eif4g

Structure:

Eukaryotic translation initiation factor 4e. Chain: a, b. Fragment: unp residues 28-217. Synonym: eif4e,eif-4f 25 kda subunit,mRNA cap-binding protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: eif4e, eif4el1, eif4f. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

1.80Å R-factor: 0.163 R-free: 0.194

Authors:

E.Papadopoulos,S.Jenni,G.Wagner

Key ref:

E.Papadopoulos et al. (2014). Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G. Proc Natl Acad Sci U S A, 111, E3187. PubMed id: 25049413 DOI: 10.1073/pnas.1410250111

Date:

10-Jun-14 Release date: 13-Aug-14

Protein chains

P06730  (IF4E_HUMAN) -  Eukaryotic translation initiation factor 4E from Homo sapiens

Seq: 217 a.a.

Struc: 176 a.a.

DOI no: 10.1073/pnas.1410250111

Proc Natl Acad Sci U S A 111:E3187 (2014)

PubMed id: 25049413

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

E.Papadopoulos, S.Jenni, E.Kabha, K.J.Takrouri, T.Yi, N.Salvi, R.E.Luna, E.Gavathiotis, P.Mahalingam, H.Arthanari, R.Rodriguez-Mias, R.Yefidoff-Freedman, B.H.Aktas, M.Chorev, J.A.Halperin, G.Wagner.

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.