PDBsum entry 5ehc

Translation

PDB id: 5ehc

Contents

Protein chains

186 a.a.

14 a.a.

Ligands

5NX

Waters ×139

PDB id:

5ehc

Name:

Translation

Title:

Co-crystal structure of eif4e with nucleotide mimetic inhibitor.

Structure:

Eukaryotic translation initiation factor 4e. Chain: a. Synonym: eif4e,eif-4f 25 kda subunit,mRNA cap-binding protein. Engineered: yes. Eukaryotic translation initiation factor 4 gamma 1. Chain: b. Fragment: eif4e binding sequence, unp residues 634-647. Synonym: eif-4g1,p220. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: eif4e, eif4el1, eif4f. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: rosetta plyss. Synthetic: yes. Other_details: commercial synthesis

Resolution:

2.40Å R-factor: 0.221 R-free: 0.264

Authors:

M.W.Nowicki,M.D.Walkinshaw,P.M.Fischer

Key ref:

F.Soukarieh et al. (2016). 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. PubMed id: 27592390

Date:

28-Oct-15 Release date: 07-Sep-16

Protein chain

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

Seq: 217 a.a.

Struc: 186 a.a.

Protein chain

Q04637  (IF4G1_HUMAN) -  Eukaryotic translation initiation factor 4 gamma 1 from Homo sapiens

Seq: 1599 a.a.

Struc: 14 a.a.

Eur J Med Chem 124:200-217 (2016)

PubMed id: 27592390

Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation.

F.Soukarieh, M.W.Nowicki, A.Bastide, T.Pöyry, C.Jones, K.Dudek, G.Patwardhan, F.Meullenet, N.J.Oldham, M.D.Walkinshaw, A.E.Willis, P.M.Fischer.

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 (m⁷GpppN, 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 N⁷-substituent of m⁷GMP 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 m⁷GMP 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-N⁷-methyl-guanosine (4a), N⁷-3-chlorobenzyl-5'-deoxy-5'-(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N⁷-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.