The Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity between eIF4A and Polypurine RNA

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.一类以分离自米仔兰属（Aglaia）植物的天然产物罗卡格莱胺A（rocaglamide A, RocA）为代表的翻译抑制剂，可通过将真核翻译起始因子4A（eukaryotic translation initiation factor 4A, eIF4A）钳定在信使RNA（mRNA）的多嘌呤序列上发挥抗肿瘤活性。这一独特的抑制机制引出了一个关键科学问题：该药物如何对广谱翻译因子施加序列选择性。本研究解析了人源eIF4A1⋅ATP类似物⋅RocA⋅多嘌呤RNA复合物的晶体结构。RocA靶向由eIF4A1与RNA中一对高度弯曲的连续嘌呤碱基特异性形成的"双分子空腔"。米仔兰属eIF4A中存在的天然氨基酸取代会改变该空腔的形态，进而导致对RocA的耐药性。本研究为一类可适配由特定序列的蛋白质与RNA协同形成的空间的RNA序列选择性界面抑制剂提供了范例。