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Mol Cell. 2015 Mar 19;57(6):1074-1087. doi: 10.1016/j.molcel.2015.01.017. Epub 2015 Feb 19.

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

Author information

1
Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
2
Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address: oliver.weichenrieder@tuebingen.mpg.de.
3
Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address: elisa.izaurralde@tuebingen.mpg.de.

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 fly 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.

PMID:
25702871
DOI:
10.1016/j.molcel.2015.01.017
[Indexed for MEDLINE]
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