9don
Crystal structure of eIF4e in complex with Compound 5-PA
Structural highlights
FunctionIF4E_HUMAN Its translation stimulation activity is repressed by binding to the complex CYFIP1-FMR1 (By similarity). Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates the binding to the mRNA cap.[1] Publication Abstract from PubMedDysregulation of translation is a hallmark of cancer that enables rapid changes in cellular protein production to shape oncogenic phenotypes. Translation initiation is governed by the m(7)GpppX cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), the rate-limiting factor of cap-dependent translation initiation. eIF4E is overexpressed in many cancers and drives the production of oncoproteins that promote tumor growth and survival. Accordingly, eIF4E has been established as an attractive albeit challenging therapeutic target. Building upon our previous work of developing cell-permeable cap analogue prodrugs that inhibit eIF4E binding to the m(7)GpppX cap, herein we disclose the design of second-generation cap analogues with alternative N-9-substituted linkers which exhibit anticancer activity in BRAF(V600E) mutant melanoma cell lines. Second-Generation Cap Analogue Prodrugs for Targeting Aberrant Eukaryotic Translation Initiation Factor 4E Activity in Cancer.,Cardenas EL, O'Rourke RL, Menon A, Vega-Hernandez G, Meagher J, Stuckey J, Garner AL ACS Med Chem Lett. 2024 Dec 12;16(1):96-100. doi: 10.1021/acsmedchemlett.4c00466. , eCollection 2025 Jan 9. PMID:39811141[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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