The SF3b Complex is an Integral Component of the Spliceosome and Targeted by Natural Product-Based Inhibitors

Larsen, Nicholas

doi:10.1007/978-3-030-58971-4_12

Cited by 11 publications

(4 citation statements)

References 96 publications

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“…SF3B1 is an ∼150 kDa member of the spliceosome and is essential for stabilizing the branch point adenosine prior to intron removal (Larsen, 2021). Natural product-based modulators of SF3B1 have been described, and these compounds show broad spectrum anti-proliferative activity (Lee and Abdel-Wahab, 2016).…”

Section: Resultsmentioning

confidence: 99%

Proteomic discovery of chemical probes that perturb protein complexes in human cells

Lazear

Remsberg

Jaeger

et al. 2022

Preprint

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Most human proteins lack chemical probes, and several large-scale and generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such binding-first assays affect protein function, nonetheless, often remains unclear. Here, we describe a function-first proteomic strategy that uses size exclusion chromatography (SEC) to assess the global impact of electrophilic compounds on protein complexes in human cells. Integrating the SEC data with cysteine-directed activity-based protein profiling identifies changes in protein-protein interactions that are caused by site-specific liganding events, including the stereoselective engagement of cysteines in PSME1 and SF3B1 that disrupt the PA28 proteasome regulatory complex and stabilize a dynamic state of the spliceosome, respectively. Our findings thus show how multidimensional proteomic analysis of focused libraries of electrophilic compounds can expedite the discovery of chemical probes with site-specific functional effects on protein complexes in human cells.

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Section: Resultsmentioning

confidence: 99%

Proteomic discovery of chemical probes that perturb protein complexes in human cells

Lazear

Remsberg

Jaeger

et al. 2022

Preprint

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“…The copyright holder for this preprint this version posted January 15, 2024. ; https://doi.org/10.1101/2024.01.14.575540 doi: bioRxiv preprint To investigate whether the motif signatures were associated with specific RNA processing functions, we used the weight matrix H to quantify the contribution of the signatures to motifs. We collected domain and functional annotations of RBPs from the previous studies [38][39][40][41][42][43][44], and the corresponding motifs were collected from ATract database [36]. Statistical analysis was performed using the Wilcoxon rank-sum test, with a significance threshold of a Benjamini-Hochberg adjusted p-value < 0.05.…”

Section: Motif Signature Constructionmentioning

confidence: 99%

Reformer: Deep learning model for characterizing protein-RNA interactions from sequence at single-base resolution

Shen,

2024

Preprint

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Protein-RNA interactions play an essential role in the regulation of transcription, translation, and metabolism of cellular RNA. Here, we develop Reformer, a deep learning model that predicts protein-RNA binding affinity purely from sequence. We developed Reformer with 155 RNA binding protein (RBP) targets from 3 cell lines. Reformer achieved high prediction accuracy at single-base resolution when tasking with inferring protein- and cell-type-specific binding affinity. We conducted electrophoretic mobility shift assays to validate high-impact RNA regulation mutations predicted by Reformer. In addition, Reformer learned to capture protein binding motifs that cannot be discovered by eCLIP-seq experiments. Furthermore, we demonstrated that motif signatures related to RNA processing functions are encoded within Reformer. In conclusion, Reformer will facilitate interpretation of the regulation mechanisms underlying RNA processing.

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“…and herboxadiene ( 2e ) (Figure ) from Streptomyces chromofuscus, respectively. All three families of natural products ( 1–2a , 2b – 2d , and 2e , Figure ) would later be united by a similar antitumor mode of action (MOA) − targeting the SF3B complex of the human spliceosome and are referred to as spliceosome modulators (SPLMs) …”

Section: Introductionmentioning

confidence: 99%

“…All three families of natural products (1−2a, 2b−2d, and 2e, Figure 1) would later be united by a similar antitumor mode of action (MOA) 9−11 targeting the SF3B complex of the human spliceosome and are referred to as spliceosome modulators (SPLMs). 12 The X-ray crystal structure of the core SF3B complex was solved by Pena in 2016, 13 followed soon after by its elucidation by cryo-EM. 14 The SF3B complex bound to pladienolide B (2a) was subsequently reported 15,16 and has since been furthered to provide detailed structures with additional analogues, including FD-895 (1).…”

Section: ■ Introductionmentioning

confidence: 99%

Stereochemical Control of Splice Modulation in FD-895 Analogues

et al. 2023

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Highly functionalized skeletons of macrolide natural products gain access to rare spatial arrangements of atoms, where changes in stereochemistry can have a profound impact on the structure and function. Spliceosome modulators present a unique consensus motif, with the majority targeting a key interface within the SF3B spliceosome complex. Our recent preparative-scale synthetic campaign of 17S-FD-895 provided unique access to stereochemical analogues of this complex macrolide. Here, we report on the preparation and systematic activity evaluation of multiple FD-895 analogues. These studies examine the effects of modifications at specific stereocenters within the molecule and highlight future directions for medicinal chemical optimization of spliceosome modulators.

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The SF3b Complex is an Integral Component of the Spliceosome and Targeted by Natural Product-Based Inhibitors

Cited by 11 publications

References 96 publications

Proteomic discovery of chemical probes that perturb protein complexes in human cells

Proteomic discovery of chemical probes that perturb protein complexes in human cells

Reformer: Deep learning model for characterizing protein-RNA interactions from sequence at single-base resolution

Stereochemical Control of Splice Modulation in FD-895 Analogues

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