Musashi-2 (MSI2) belongs to Musashi family of RNA binding proteins (RBP). Like Musashi-1 (MSI1), it is overexpressed in a variety of cancers and is a promising therapeutic target. Both MSI proteins contain two N-terminal RNA recognition motifs and play roles in posttranscriptional regulation of target mRNAs. Previously, we have identified several inhibitors of MSI1, all of which bind to MSI2 as well. In order to design MSI2-specific inhibitors and compare the differences of binding mode of the inhibitors, we set out to solve the structure of MSI2-RRM1, the key motif that is responsible for the binding. Here, we report the crystal structure and the first NMR solution structure of MSI2-RRM1, and compare these to the structures of MSI1-RBD1 and other RBPs. A high degree of structural similarity was observed between the crystal and solution NMR structures. MSI2-RRM1 shows a highly similar overall folding topology to MSI1-RBD1 and other RBPs. The structural information of MSI2-RRM1 will be helpful for understanding MSI2-RNA interaction and for guiding rational drug design of MSI2-specific inhibitors.

中文翻译：

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人癌蛋白Musashi-2 N端RNA识别基序的晶体和溶液结构1。

Musashi-2（MSI2）属于Musashi RNA结合蛋白（RBP）家族。像Musashi-1（MSI1）一样，它在多种癌症中都过表达，并且是有希望的治疗靶标。这两种MSI蛋白均包含两个N端RNA识别基序，并在转录后调控靶mRNA的过程中发挥作用。以前，我们已经确定了几种MSI1抑制剂，它们全部也与MSI2结合。为了设计MSI2特异性抑制剂并比较抑制剂结合模式的差异，我们着手解决MSI2-RRM1的结构，MSI2-RRM1是负责结合的关键基序。在这里，我们报告MSI2-RRM1的晶体结构和第一个NMR溶液结构，并将它们与MSI1-RBD1和其他RBP的结构进行比较。在晶体和溶液NMR结构之间观察到高度的结构相似性。MSI2-RRM1显示出与MSI1-RBD1和其他RBP高度相似的整体折叠拓扑。MSI2-RRM1的结构信息将有助于理解MSI2-RNA相互作用，并指导MSI2特异性抑制剂的合理药物设计。