8QM7

Potential drug binding sites for translation initiation factor eIF4E

Summary for 8QM7

• Entry DOI: 10.2210/pdb8qm7/pdb
• Descriptor: Eukaryotic translation initiation factor 4E, DIMETHYL SULFOXIDE, TRIETHYLENE GLYCOL, ... (6 entities in total)
• Functional Keywords: translation initiation factor, translation regulator, protein biosynthesis, rna binding, translation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 51214.43

Authors

Cleasby, A. (deposition date: 2023-09-21, release date: 2025-01-15, Last modification date: 2025-03-12)

Primary citation

Sharp, S.Y.,Martella, M.,D'Agostino, S.,Milton, C.I.,Ward, G.,Woodhead, A.J.,Richardson, C.J.,Carr, M.G.,Chiarparin, E.,Cons, B.D.,Coyle, J.,East, C.E.,Hiscock, S.D.,Martinez-Fleites, C.,Mortenson, P.N.,Palmer, N.,Pathuri, P.,Powers, M.V.,Saalau, S.M.,St Denis, J.D.,Swabey, K.,Vinkovic, M.,Walton, H.,Williams, G.,Clarke, P.A.
Integrating fragment-based screening with targeted protein degradation and genetic rescue to explore eIF4E function.
Nat Commun, 15:10037-10037, 2024

PubMed Abstract: Eukaryotic initiation factor 4E (eIF4E) serves as a regulatory hub for oncogene-driven protein synthesis and is considered a promising anticancer target. Here we screen a fragment library against eIF4E and identify a ligand-binding site with previously unknown function. Follow-up structure-based design yields a low nM tool compound (4, K = 0.09 µM; LE 0.38), which disrupts the eIF4E:eIF4G interaction, inhibits translation in cell lysates, and demonstrates target engagement with eIF4E in intact cells (EC = 2 µM). By coupling targeted protein degradation with genetic rescue using eIF4E mutants, we show that disruption of both the canonical eIF4G and non-canonical binding sites is likely required to drive a strong cellular effect. This work highlights the power of fragment-based drug discovery to identify pockets in difficult-to-drug proteins and how this approach can be combined with genetic characterization and degrader technology to probe protein function in complex biological systems.

PubMed: 40016190
DOI: 10.1038/s41467-024-54356-1

Experimental method

X-RAY DIFFRACTION (2.191 Å)