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

Lan, Lan; Xing, Minli; Kashipathy, M.M.; Douglas, Justin T.; Gao, Philip; Battaile, K.P.; Hanzlik, Robert P.; Lovell, Scott; Xu, Liang

doi:10.1002/prot.25836

Cited by 10 publications

(16 citation statements)

References 69 publications

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“…Similarly, MSI1 has two separate RRMs structures [165,166]. MIS2 only has RRM1 structures published [158,167]. Most of the HuR/ARE disruptors target the RRM1-2, while the sole RRM3 ligand has shown weak interference with full-length HuR/ARE complex [122].…”

Section: Other Molecules Identified From Hts Targeting Msi/rna and Comentioning

confidence: 99%

RNA-Targeted Therapies and High-Throughput Screening Methods

Zhu

Rooney

Michlewski

2020

IJMS

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RNA-binding proteins (RBPs) are involved in regulating all aspects of RNA metabolism, including processing, transport, translation, and degradation. Dysregulation of RNA metabolism is linked to a plethora of diseases, such as cancer, neurodegenerative diseases, and neuromuscular disorders. Recent years have seen a dramatic shift in the knowledge base, with RNA increasingly being recognised as an attractive target for precision medicine therapies. In this article, we are going to review current RNA-targeted therapies. Furthermore, we will scrutinise a range of drug discoveries targeting protein-RNA interactions. In particular, we will focus on the interplay between Lin28 and let-7, splicing regulatory proteins and survival motor neuron (SMN) pre-mRNA, as well as HuR, Musashi, proteins and their RNA targets. We will highlight the mechanisms RBPs utilise to modulate RNA metabolism and discuss current high-throughput screening strategies. This review provides evidence that we are entering a new era of RNA-targeted medicine.

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Section: Other Molecules Identified From Hts Targeting Msi/rna and Comentioning

confidence: 99%

RNA-Targeted Therapies and High-Throughput Screening Methods

Zhu

Rooney

Michlewski

2020

IJMS

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“…Rational design of small molecules targeting protein-RNA interactions requires structural characterizations of the RBP-RNA complexes. Due to high flexibility of MSI proteins and lack of potent ligands, only a few MSI structures have been resolved so far, including the apo structure of MSI1/2-RRM1 ( Lan et al., 2020 ; Lan et al., 2017 ; Nagata et al., 1999 ; Miyanoiri et al., 2003 ; Minuesa et al., 2019 ) and RNA-bound structure of MSI1 ( Ohyama et al., 2011 ; Iwaoka et al., 2017 ). These structures have greatly facilitated structure-based modeling and drug design targeting the MSI-RNA interactions ( Lan et al., 2015 ; Clingman et al., 2014 ; Lan et al., 2018 ; Lan et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Due to high flexibility of MSI proteins and lack of potent ligands, only a few MSI structures have been resolved so far, including the apo structure of MSI1/2-RRM1 ( Lan et al., 2020 ; Lan et al., 2017 ; Nagata et al., 1999 ; Miyanoiri et al., 2003 ; Minuesa et al., 2019 ) and RNA-bound structure of MSI1 ( Ohyama et al., 2011 ; Iwaoka et al., 2017 ). These structures have greatly facilitated structure-based modeling and drug design targeting the MSI-RNA interactions ( Lan et al., 2015 ; Clingman et al., 2014 ; Lan et al., 2018 ; Lan et al., 2020 ). For example, we have recently identified one potent compound Aza-9 by combining fluorescence polarization (FP) assay, surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) spectroscopy and molecular docking ( Lan et al., 2020a , Lan et al., 2020b ).…”

Section: Introductionmentioning

confidence: 99%

“…These structures have greatly facilitated structure-based modeling and drug design targeting the MSI-RNA interactions ( Lan et al., 2015 ; Clingman et al., 2014 ; Lan et al., 2018 ; Lan et al., 2020 ). For example, we have recently identified one potent compound Aza-9 by combining fluorescence polarization (FP) assay, surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) spectroscopy and molecular docking ( Lan et al., 2020a , Lan et al., 2020b ). However, experimental structures are rather static images and the dynamic mechanism of MSI-RNA interactions remains unknown, which has largely hindered the development of potent inhibitors of MSI proteins.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of RNA recognition by a Musashi RNA-binding protein

Wang

Lan

et al. 2022

Current Research in Structural Biology

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The Musashi RNA-binding proteins (RBPs) regulate translation of target mRNAs and maintenance of cell stemness and tumorigenesis. Musashi-1 (MSI1), long considered as an intestinal and neural stem cell marker, has been more recently found to be over expressed in many cancers. It has served as an important drug target for treating acute myeloid leukemia and solid tumors such as ovarian, colorectal and bladder cancer. One of the reported binding targets of MSI1 is Numb, a negative regulator of the Notch signaling. However, the dynamic mechanism of Numb RNA binding to MSI1 remains unknown, largely hindering effective drug design targeting this critical interaction. Here, we have performed extensive all-atom microsecond-timescale simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method, which successfully captured multiple times of spontaneous and highly accurate binding of the Numb RNA from bulk solvent to the MSI1 protein target site. GaMD simulations revealed that Numb RNA binding to MSI1 involved largely induced fit in both the RNA and protein. The simulations also identified important low-energy intermediate conformational states during RNA binding, in which Numb interacted mainly with the β2-β3 loop and C terminus of MSI1. The mechanistic understanding of RNA binding obtained from our GaMD simulations is expected to facilitate rational structure-based drug design targeting MSI1 and other RBPs.

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“…Rational design of small molecules targeting protein-RNA interactions requires structural characterizations of the RBP-RNA complexes. Due to high flexibility of MSI proteins and the lack of potent ligands, only a few MSI structures have been resolved so far, including the apo structure of MSI1/2-RRM1 [6][7][8][9][10] and RNA-bound structure of MSI1 [11][12] . These structures have greatly facilitated structure-based modeling and drug design targeting the MSI-RNA interactions [13][14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Mechanism of RNA recognition by a Musashi RNA-binding protein

Wang

Lan

et al. 2020

Preprint

Self Cite

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The Musashi RNA-binding proteins (RBPs) regulate translation of target mRNAs and maintenance of cell stemness and tumorigenesis. Musashi-1 (MSI1), long considered as an intestinal and neural stem cell marker, has been more recently found to be overexpressed in many cancers. It has served as an important drug target for treating acute myeloid leukemia and solid tumors such as ovarian, colorectal and bladder cancer. One of the reported binding targets of MSI1 is Numb, a negative regulator of the Notch signaling. However, the dynamic mechanism of Numb RNA binding to MSI1 remains unknown, largely hindering effective drug design targeting this critical interaction. Here, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method, which successfully captured spontaneous and highly accurate binding of the Numb RNA from bulk solvent to the MSI1 protein target site. GaMD simulations revealed that Numb binding to MSI1 involved largely induced fit in both the RNA and protein. The simulations also identified important low-energy intermediate conformational states during RNA binding, in which Numb interacted mainly with the β2-β3 loop and C terminus of MSI1. The mechanistic understanding of RNA binding obtained from our GaMD simulations is expected to facilitate rational structure-based drug design targeting MSI1 and other RBPs.

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

Cited by 10 publications

References 69 publications

RNA-Targeted Therapies and High-Throughput Screening Methods

RNA-Targeted Therapies and High-Throughput Screening Methods

Mechanism of RNA recognition by a Musashi RNA-binding protein

Mechanism of RNA recognition by a Musashi RNA-binding protein

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