Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

Lan, Lan; Xing, Minli; Kashipathy, Maithri; Douglas, Justin; Gao, Philip; Battaile, Kevin; Hanzlik, Robert; Lovell, Scott; Xu, Liang

doi:10.1002/prot.25836

Title: Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

Journal Article · 29 October 2019 · Proteins

DOI: https://doi.org/10.1002/prot.25836 · OSTI ID:1572211

^[1]; Xing, Minli ^[2]; Kashipathy, Maithri ^[3]; Douglas, Justin ^[2]; Gao, Philip ^[4]; Battaile, Kevin ^[5]; Hanzlik, Robert ^[6]; Lovell, Scott ^[3];

^[7]

Department of Molecular Biosciences The University of Kansas Lawrence Kansas
Bio‐NMR Core Facility, NIH COBRE in Protein Structure and Function, The University of Kansas Lawrence Kansas
Protein Structure Laboratory, NIH COBRE in Protein Structure and Function, The University of Kansas Lawrence Kansas
Protein Production Group, NIH COBRE in Protein Structure and Function The University of Kansas Lawrence Kansas
IMCA‐CAT Hauptman Woodward Medical Research Institute Argonne Illinois
Department of Medicinal Chemistry The University of Kansas Lawrence Kansas
Department of Molecular Biosciences The University of Kansas Lawrence Kansas, Department of Radiation Oncology The University of Kansas Cancer Center Kansas City Kansas

Abstract 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOD; USDOE; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1572211

Journal Information:: Proteins, Journal Name: Proteins Journal Issue: 4 Vol. 88; ISSN 0887-3585

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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crystallography
nuclear magnetic resonance

Title: Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

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