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4ue8

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Complex of D. melanogaster eIF4E with the 4E binding protein Thor

Structural highlights

4ue8 is a 2 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.1Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IF4E_DROME 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.^[1]

Publication Abstract from PubMed

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.

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 Mol Cell. 2015 Feb 18. pii: S1097-2765(15)00018-0. doi:, 10.1016/j.molcel.2015.01.017. PMID:25702871^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lavoie CA, Lachance PE, Sonenberg N, Lasko P. Alternatively spliced transcripts from the Drosophila eIF4E gene produce two different Cap-binding proteins. J Biol Chem. 1996 Jul 5;271(27):16393-8. PMID:8663200
↑ Peter D, Igreja C, Weber R, Wohlbold L, Weiler C, Ebertsch L, Weichenrieder O, Izaurralde E. Molecular Architecture of 4E-BP Translational Inhibitors Bound to eIF4E. Mol Cell. 2015 Feb 18. pii: S1097-2765(15)00018-0. doi:, 10.1016/j.molcel.2015.01.017. PMID:25702871 doi:http://dx.doi.org/10.1016/j.molcel.2015.01.017