4DUM

Co-crystal structure of eIF4E with inhibitor

Summary for 4DUM

• Entry DOI: 10.2210/pdb4dum/pdb
• Related: 4DT6
• Descriptor: Eukaryotic translation initiation factor 4E, (4-{7-[2-(4-chlorophenoxy)ethyl]-2-(methylamino)-6-oxo-6,7-dihydro-1H-purin-8-yl}phenyl)phosphonic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: cap-binding protein, translation initiation factor, m7gtp, translation
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, P-body: P06730
• Total number of polymer chains: 1
• Total formula weight: 28640.26

Authors

Min, X.,Johnstone, S.,Walker, N.,Wang, Z. (deposition date: 2012-02-22, release date: 2012-04-11, Last modification date: 2024-02-28)

Primary citation

Chen, X.,Kopecky, D.J.,Mihalic, J.,Jeffries, S.,Min, X.,Heath, J.,Deignan, J.,Lai, S.,Fu, Z.,Guimaraes, C.,Shen, S.,Li, S.,Johnstone, S.,Thibault, S.,Xu, H.,Cardozo, M.,Shen, W.,Walker, N.,Kayser, F.,Wang, Z.
Structure-Guided Design, Synthesis, and Evaluation of Guanine-Derived Inhibitors of the eIF4E mRNA-Cap Interaction.
J.Med.Chem., 55:3837-3851, 2012

PubMed Abstract: The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC(50) of 2.5 μM for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.

PubMed: 22458568
DOI: 10.1021/jm300037x

Experimental method

X-RAY DIFFRACTION (2.95 Å)