1. Molecular architecture of 4E-BP translational inhibitors bound to eIF4E.
- Author
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Peter D, Igreja C, Weber R, Wohlbold L, Weiler C, Ebertsch L, Weichenrieder O, and Izaurralde E
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Amino Acid Motifs, Animals, Binding Sites, Binding, Competitive, Carrier Proteins chemistry, Carrier Proteins genetics, Carrier Proteins metabolism, Cell Cycle Proteins, Crystallography, X-Ray, Drosophila Proteins genetics, Drosophila Proteins metabolism, Eukaryotic Initiation Factor-4G metabolism, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Models, Molecular, Molecular Mimicry, Peptide Initiation Factors genetics, Peptide Initiation Factors metabolism, Phosphoproteins metabolism, Phosphorylation, Protein Conformation, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Adaptor Proteins, Signal Transducing chemistry, Drosophila Proteins chemistry, Eukaryotic Initiation Factor-4E chemistry, Eukaryotic Initiation Factor-4E metabolism, Eukaryotic Initiation Factor-4G chemistry, Intracellular Signaling Peptides and Proteins chemistry, Peptide Initiation Factors chemistry, Phosphoproteins chemistry
- 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., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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