Abstract 4140: Dissecting the structural basis for rational inhibitor design: Crystal and solution structures of human oncoprotein Musashi-2 N-terminal RNA recognition motif 1

Abstract

Abstract RNA-binding proteins (RBPs) are key regulators of cellular functions, especially in post-transcriptional regulations. Dysregulation of RBPs is implicated in many diseases including cancer. One of the RBPs that is overexpressed in a variety of human cancer is Musashi-2 (MSI2). Elevated MSI2 expression is associated with ectopic oncogenic pathways including but not limited to NUMB/Notch, PTEN/mTOR, TGF-β/SMAD3, making MSI2 a promising therapeutic target for cancer. Protein structure is critical for drug discovery and structure-based rational design. Both MSI1 and MSI2 proteins contain two N-terminal RNA recognition motifs and play roles in post-transcriptional regulation of target mRNAs. 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 RNA binding proteins. 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 RNA binding proteins. The structural information of MSI2-RRM1 will be helpful for understanding MSI2-RNA interaction and for guiding rational design of MSI2 specific inhibitors. Citation Format: Lan Lan, Minli Xing, Maithri Kashipathy, Justin Douglas, Philip Gao, Kevin Battaile, Robert Hanzlik, Scott Lovell, Liang Xu. Dissecting the structural basis for rational inhibitor design: Crystal and solution structures of human oncoprotein Musashi-2 N-terminal RNA recognition motif 1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4140.