Molecular architecture of 4E-BP translational inhibitors bound to eIF4E

Peter, D; Igreja, C; Weber, R; Wohlbold, L; Weiler, C; Ebertsch, L; Weichenrieder, O; Izaurralde, E

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Molecular architecture of 4E-BP translational inhibitors bound to eIF4E

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Peter, D
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

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Igreja, C
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;
Regulation and Post-Translational Modification of Gene Expression in Nematodes Group, Department Integrative Evolutionary Biology, Max Planck Institute for Developmental Biology, Max Planck Society;

/persons/resource/persons272040

Weber, R
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

/persons/resource/persons273100

Wohlbold, L
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

/persons/resource/persons275388

Weiler, C
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

/persons/resource/persons275277

Ebertsch, L
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

/persons/resource/persons271778

Weichenrieder, O
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;
Retrotransposition and Regulatory RNAs Group, Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

/persons/resource/persons271767

Izaurralde, E
Department Biochemistry, Max Planck Institute for Developmental Biology, Max Planck Society;

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https://www2.rnasociety.org/wp-content/uploads/2015/05/RNA-2015-Abstract-Book-print-150505.pdf
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Citation

Peter, D., Igreja, C., Weber, R., Wohlbold, L., Weiler, C., Ebertsch, L., et al. (2015). Molecular architecture of 4E-BP translational inhibitors bound to eIF4E. In Twentieth Annual Meeting of the RNA Society (pp. 116).

Cite as: https://hdl.handle.net/21.11116/0000-000D-B532-E

Abstract

The eIF4E-binding proteins (4E-BPs) represent a diverse class of translation inhibitors that are often deregulated in cancer cells. 4E-BPs inhibit translation by competing with eIF4G for binding to eIF4E through an interface that consists of canonical and non-canonical eIF4E-binding motifs connected by a linker. The lack of high-resolution structures including the linkers, which contain phosphorylation sites, limits our understanding of how phosphorylation inhibits complex formation. Furthermore, the binding mechanism of the non-canonical motifs is poorly understood. Here, we present structures of human eIF4E bound to 4E-BP1 and flie eIF4E bound to Thor, 4E-T and eIF4G. These structures reveal architectural elements that are unique to 4E-BPs and provide insight into the consequences of phosphorylation. Guided by these structures, we designed and crystallized a 4E-BP mimic that shows increased repressive activity. Our studies pave the way for the rational design of 4E-BP mimics as therapeutic tools to decrease translation during oncogenic transformation.