Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 277-8561, Japan.
Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama 230-0045, Japan; Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Tsurumi-ku, Yokohama 230-0045, Japan.
Mol Cell. 2019 Feb 21;73(4):738-748.e9. doi: 10.1016/j.molcel.2018.11.026. Epub 2018 Dec 27.
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.
一类翻译抑制剂，以天然产物罗卡酰胺 A（RocA）为代表，从 Aglaia 属植物中分离出来，通过将真核翻译起始因子 4A（eIF4A）夹在 mRNA 中的多嘧啶序列上来发挥抗肿瘤活性。这种不寻常的抑制机制提出了一个问题，即药物如何将序列选择性施加于通用翻译因子。在这里，我们确定了人 eIF4A1·ATP 类似物·RocA·多嘧啶 RNA 复合物的晶体结构。RocA 靶向由 eIF4A1 和 RNA 中一对连续的强烈弯曲嘧啶形成的特征性“双分子腔”。在 Aglaia eIF4A 中发现的天然氨基酸取代改变了腔的形状，导致 RocA 耐药。这项研究提供了一个例子，说明 RNA 序列选择性界面抑制剂适合与具有特定序列的蛋白质和 RNA 共同形成的空间。
