5EHC

Co-crystal structure of eIF4E with nucleotide mimetic inhibitor.

Summary for 5EHC

• Entry DOI: 10.2210/pdb5ehc/pdb
• Related: 2V8W
• Descriptor: Eukaryotic translation initiation factor 4E, Eukaryotic translation initiation factor 4 gamma 1, 3-[[(2~{R},3~{S},4~{R},5~{R})-5-[2-azanyl-7-[(3-chlorophenyl)methyl]-6-oxidanylidene-1~{H}-purin-7-ium-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methylamino]-4-oxidanyl-cyclobut-3-ene-1,2-dione, ... (4 entities in total)
• Functional Keywords: complex, inhibitor, translation, eif4e
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm, P-body : P06730
• Total number of polymer chains: 2
• Total formula weight: 27485.27

Authors

Nowicki, M.W.,Walkinshaw, M.D.,Fischer, P.M. (deposition date: 2015-10-28, release date: 2016-09-07, Last modification date: 2024-01-10)

Primary citation

Soukarieh, F.,Nowicki, M.W.,Bastide, A.,Poyry, T.,Jones, C.,Dudek, K.,Patwardhan, G.,Meullenet, F.,Oldham, N.J.,Walkinshaw, M.D.,Willis, A.E.,Fischer, P.M.
Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation.
Eur.J.Med.Chem., 124:200-217, 2016

PubMed Abstract: Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 5'-terminal mRNA cap structure (mGpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design cap-binding inhibitors of eIF4E by modifying the N-substituent of mGMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N-[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5-g]quinolin-7-yl)methyl]-N'-(2-methyl-propyl)-N-(phenyl-methyl)thiourea (14), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified mGMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 5'-deoxy-5'-(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N-methyl-guanosine (4a), N-3-chlorobenzyl-5'-deoxy-5'-(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N-benzyl-5'-deoxy-5'-(trifluoromethyl-sulfamoyl)guanosine (7a). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents.

PubMed: 27592390
DOI: 10.1016/j.ejmech.2016.08.047

Experimental method

X-RAY DIFFRACTION (2.4 Å)