5ZC9

Crystal structure of the human eIF4A1-ATP analog-RocA-polypurine RNA complex

Summary for 5ZC9

• Entry DOI: 10.2210/pdb5zc9/pdb
• Descriptor: Eukaryotic initiation factor 4A-I, RNA (5'-R(*AP*GP*AP*GP*AP*GP*AP*GP*AP*G)-3'), PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (6 entities in total)
• Functional Keywords: initiation factor, dead-box, helicase, protein-rna complex, atpase, rocaglamide a, anticancer compound, translation, translation-rna complex, translation/rna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 49264.61

Authors

Iwasaki, W.,Takahashi, M.,Sakamoto, A.,Iwasaki, S.,Ito, T. (deposition date: 2018-02-16, release date: 2019-01-16, Last modification date: 2023-11-22)

Primary citation

Iwasaki, S.,Iwasaki, W.,Takahashi, M.,Sakamoto, A.,Watanabe, C.,Shichino, Y.,Floor, S.N.,Fujiwara, K.,Mito, M.,Dodo, K.,Sodeoka, M.,Imataka, H.,Honma, T.,Fukuzawa, K.,Ito, T.,Ingolia, N.T.
The Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity between eIF4A and Polypurine RNA.
Mol. Cell, 73:738-, 2019

PubMed Abstract: A class of translation inhibitors, exemplified by the natural product rocaglamide A (RocA), isolated from Aglaia genus plants, exhibits antitumor activity by clamping eukaryotic translation initiation factor 4A (eIF4A) onto polypurine sequences in mRNAs. This unusual inhibitory mechanism raises the question of how the drug imposes sequence selectivity onto a general translation factor. Here, we determined the crystal structure of the human eIF4A1⋅ATP analog⋅RocA⋅polypurine RNA complex. RocA targets the "bi-molecular cavity" formed characteristically by eIF4A1 and a sharply bent pair of consecutive purines in the RNA. Natural amino acid substitutions found in Aglaia eIF4As changed the cavity shape, leading to RocA resistance. This study provides an example of an RNA-sequence-selective interfacial inhibitor fitting into the space shaped cooperatively by protein and RNA with specific sequences.

PubMed: 30595437
DOI: 10.1016/j.molcel.2018.11.026

Experimental method

X-RAY DIFFRACTION (2 Å)