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

Larsen, Nicholas A

2020 Volume 96, Page(s) 409–432

Abstract: In this chapter, the essential role of the SF3b multi-protein complex will be discussed in the context of the overall spliceosome. SF3b is critical during spliceosome assembly for recognition of the branch point (BP) adenosine and, by de facto, selection ...

Abstract	In this chapter, the essential role of the SF3b multi-protein complex will be discussed in the context of the overall spliceosome. SF3b is critical during spliceosome assembly for recognition of the branch point (BP) adenosine and, by de facto, selection of the 3' splice site. This complex is highly dynamic, undergoing significant conformational changes upon loading of the branch duplex RNA and in its relative positioning during spliceosomal remodeling from the A, pre-B, B, B
MeSH term(s)	Biological Products/pharmacology ; Hematologic Neoplasms/drug therapy ; Humans ; Multiprotein Complexes/antagonists & inhibitors ; Multiprotein Complexes/genetics ; RNA Precursors/genetics ; RNA Precursors/metabolism ; RNA Splicing ; Spliceosomes/chemistry ; Spliceosomes/drug effects ; Spliceosomes/genetics ; Spliceosomes/metabolism
Chemical Substances	Biological Products ; Multiprotein Complexes ; RNA Precursors
Language	English
Publishing date	2020-11-02
Publishing country	United States
Document type	Journal Article ; Review
ISSN	0306-0225 ; 0096-8757
ISSN	0306-0225 ; 0096-8757
DOI	10.1007/978-3-030-58971-4_12
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Article ; Online: Identification of 2-Sulfonyl/Sulfonamide Pyrimidines as Covalent Inhibitors of WRN Using a Multiplexed High-Throughput Screening Assay.

Parker, Mackenzie J / Lee, Hyelee / Yao, Shihua / Irwin, Sean / Hwang, Sunil / Belanger, Kylie / de Mare, Sofia Woo / Surgenor, Richard / Yan, Lu / Gee, Patricia / Morla, Shravan / Puyang, Xiaoling / Hsiao, Peng / Zeng, Hao / Zhu, Ping / Korpal, Manav / Dransfield, Paul / Bolduc, David M / Larsen, Nicholas A

Biochemistry

2023 Volume 62, Issue 14, Page(s) 2147–2160

Abstract: Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers ... ...

Abstract	Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers characterized by genomic microsatellite instability resulting from defects in DNA mismatch repair pathways. WRN's helicase activity is essential for the viability of these high microsatellite instability (MSI-H) cancers and thus presents a therapeutic opportunity. To this end, we developed a multiplexed high-throughput screening assay that monitors exonuclease, ATPase, and helicase activities of full-length WRN. This screening campaign led to the discovery of 2-sulfonyl/sulfonamide pyrimidine derivatives as novel covalent inhibitors of WRN helicase activity. The compounds are specific for WRN versus other human RecQ family members and show competitive behavior with ATP. Examination of these novel chemical probes established the sulfonamide NH group as a key driver of compound potency. One of the leading compounds, H3B-960, showed consistent activities in a range of assays (IC
MeSH term(s)	Humans ; Werner Syndrome ; Exodeoxyribonucleases/genetics ; RecQ Helicases/genetics ; RecQ Helicases/metabolism ; High-Throughput Screening Assays ; Microsatellite Instability ; Werner Syndrome Helicase/metabolism ; Neoplasms
Chemical Substances	Exodeoxyribonucleases (EC 3.1.-) ; RecQ Helicases (EC 3.6.4.12) ; Werner Syndrome Helicase (EC 3.6.4.12) ; WRN protein, human (EC 3.6.4.12)
Language	English
Publishing date	2023-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.2c00599
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Article ; Online: Biochemical and structural basis for the pharmacological inhibition of nuclear hormone receptor PPARγ by inverse agonists.

Irwin, Sean / Karr, Craig / Furman, Craig / Tsai, Jennifer / Gee, Patricia / Banka, Deepti / Wibowo, Ardian S / Dementiev, Alexey A / O'Shea, Morgan / Yang, Joyce / Lowe, Jason / Mitchell, Lorna / Ruppel, Sabine / Fekkes, Peter / Zhu, Ping / Korpal, Manav / Larsen, Nicholas A

The Journal of biological chemistry

2022 Volume 298, Issue 11, Page(s) 102539

Abstract: Recent studies have reported that the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is activated in approximately 40% of patients with muscle-invasive bladder cancer. This led us to investigate pharmacological repression of PPARγ as a ... ...

Abstract	Recent studies have reported that the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is activated in approximately 40% of patients with muscle-invasive bladder cancer. This led us to investigate pharmacological repression of PPARγ as a possible intervention strategy. Here, we characterize PPARγ antagonists and inverse agonists and find that the former behave as silent ligands, whereas inverse agonists (T0070907 and SR10221) repress downstream PPARγ target genes leading to growth inhibition in bladder cancer cell lines. To understand the mechanism, we determined the ternary crystal structure of PPARγ bound to T0070907 and the corepressor (co-R) peptide NCOR1. The structure shows that the AF-2 helix 12 (H12) rearranges to bind inside the ligand-binding domain, where it forms stabilizing interactions with the compound. This dramatic movement in H12 unveils a large interface for co-R binding. In contrast, the crystal structure of PPARγ bound to a SR10221 analog shows more subtle structural differences, where the compound binds and pushes H12 away from the ligand-binding domain to allow co-R binding. Interestingly, we found that both classes of compound promote recruitment of co-R proteins in biochemical assays but with distinct conformational changes in H12. We validate our structural models using both site-directed mutagenesis and chemical probes. Our findings offer new mechanistic insights into pharmacological modulation of PPARγ signaling.
MeSH term(s)	Humans ; PPAR gamma/metabolism ; Ligands ; Urinary Bladder Neoplasms ; Benzamides/pharmacology
Chemical Substances	PPAR gamma ; T 0070907 ; Ligands ; Benzamides
Language	English
Publishing date	2022-09-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2022.102539
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Article ; Online: Structural basis of intron selection by U2 snRNP in the presence of covalent inhibitors.

Cretu, Constantin / Gee, Patricia / Liu, Xiang / Agrawal, Anant / Nguyen, Tuong-Vi / Ghosh, Arun K / Cook, Andrew / Jurica, Melissa / Larsen, Nicholas A / Pena, Vladimir

Nature communications

2021 Volume 12, Issue 1, Page(s) 4491

Abstract: Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing modulators alter the splicing patterns in cells by binding to ... ...

Abstract	Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing modulators alter the splicing patterns in cells by binding to the U2 snRNP (small nuclear ribonucleoprotein)-a complex chaperoning the selection of branch and 3' splice sites. Here we report crystal structures of the SF3B module of the U2 snRNP in complex with spliceostatin and sudemycin FR901464 analogs, and the cryo-electron microscopy structure of a cross-exon prespliceosome-like complex arrested with spliceostatin A. The structures reveal how modulators inactivate the branch site in a sequence-dependent manner and stall an E-to-A prespliceosome intermediate by covalent coupling to a nucleophilic zinc finger belonging to the SF3B subunit PHF5A. These findings support a mechanism of intron recognition by the U2 snRNP as a toehold-mediated strand invasion and advance an unanticipated drug targeting concept.
MeSH term(s)	Cryoelectron Microscopy ; Crystallography, X-Ray ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; Humans ; Introns/genetics ; Lactones/chemistry ; Lactones/metabolism ; Models, Molecular ; Nucleic Acid Conformation ; Protein Binding ; Protein Conformation ; Pyrans/chemistry ; Pyrans/metabolism ; Pyrones/chemistry ; Pyrones/metabolism ; Ribonucleoprotein, U2 Small Nuclear/chemistry ; Ribonucleoprotein, U2 Small Nuclear/metabolism ; Spiro Compounds/chemistry ; Spiro Compounds/metabolism ; Spliceosomes/metabolism ; Spliceosomes/ultrastructure
Chemical Substances	FR 901464 ; Lactones ; Pyrans ; Pyrones ; Ribonucleoprotein, U2 Small Nuclear ; Spiro Compounds ; spliceostatin A ; spliceostatin E ; DNA (9007-49-2)
Language	English
Publishing date	2021-07-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-24741-1
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Article: Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1.

Rolfe, Alan / Yao, Shihua / Nguyen, Toung-Vi / Omoto, Kiyoyuki / Colombo, Federico / Virrankoski, Milena / Vaillancourt, Frédéric H / Yu, Lihua / Cook, Andrew / Reynolds, Dominic / Ioannidis, Stephanos / Zhu, Ping / Larsen, Nicholas A / Bolduc, David M

ACS medicinal chemistry letters

2020 Volume 11, Issue 6, Page(s) 1305–1309

Abstract: Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity ... ...

Abstract	Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity may prevent the accumulation of toxic levels of intratumoral ammonia to support tumor growth. Herein we report the discovery of a novel series of potent and selective small-molecule inhibitors of CPS1. Piperazine
Language	English
Publishing date	2020-05-26
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.0c00145
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Article: Crystal structure of the spindle assembly checkpoint protein Bub3.

Larsen, Nicholas A / Harrison, Stephen C

Journal of molecular biology

2004 Volume 344, Issue 4, Page(s) 885–892

Abstract: Bub3 is one of at least six proteins that transmit the spindle assembly checkpoint signal. These proteins delay cell cycle progression from metaphase to anaphase in response to attachment defects between kinetochores and spindle microtubules and to ... ...

Abstract	Bub3 is one of at least six proteins that transmit the spindle assembly checkpoint signal. These proteins delay cell cycle progression from metaphase to anaphase in response to attachment defects between kinetochores and spindle microtubules and to tension defects between sister chromatids. To explore the molecular interactions mediated by Bub3, we have determined the crystal structure of the Saccharomyces cerevisiae protein Bub3p at 2.35 A resolution. Bub3p is a seven-blade beta-propeller, although its sequence diverges from that of other WD40 family members. Several loops are substantially elongated, but extra domains or insertions are not present at the termini. In particular, two extended loops project from the top face of the propeller, forming a cleft. Amino acid residues across the top face and one aspect of the lateral surface (spanning blades 5-6) are highly conserved among Bub3 proteins. We propose that these conserved surfaces are the loci for key interactions with conserved motifs in spindle checkpoint proteins Bub1 and Mad3/BubR1. Comparison of the Bub3 sequence to the WD40 protein, Rae1, shows high sequence conservation along the same surfaces. Rae1 interaction with Bub1 is, therefore, likely to involve a similar mode of binding.
MeSH term(s)	Amino Acid Sequence ; Binding Sites ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/isolation & purification ; Cell Cycle Proteins/metabolism ; Crystallography, X-Ray ; Models, Molecular ; Molecular Sequence Data ; Nuclear Matrix-Associated Proteins/chemistry ; Nuclear Pore Complex Proteins ; Nucleocytoplasmic Transport Proteins/chemistry ; Protein Binding ; Protein Structure, Tertiary ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/isolation & purification ; Saccharomyces cerevisiae Proteins/metabolism ; Sequence Alignment ; Spindle Apparatus/metabolism
Chemical Substances	BUB3 protein, S cerevisiae ; Cell Cycle Proteins ; GLE2 protein, S cerevisiae ; Nuclear Matrix-Associated Proteins ; Nuclear Pore Complex Proteins ; Nucleocytoplasmic Transport Proteins ; Saccharomyces cerevisiae Proteins
Language	English
Publishing date	2004-12-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2004.09.094
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Article: Effectiveness of Reduced Rates of Insecticides for the Control of Melanotus communis (Coleoptera: Elateridae) in Sugarcane

Larsen, Nicholas A / Nuessly, Gregg S

Florida entomologist. 2009 Dec., v. 92, no. 4

2009

Keywords	Melanotus communis ; phorate ; ethoprophos ; application rate ; pesticide use reduction ; Saccharum ; sugarcane ; soil types ; population density ; crop damage ; insect control
Language	English
Dates of publication	2009-12
Size	p. 629-634.
Document type	Article
ZDB-ID	1439588-5
ISSN	0015-4040
ISSN	0015-4040
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The R882H DNMT3A hot spot mutation stabilizes the formation of large DNMT3A oligomers with low DNA methyltransferase activity.

Nguyen, Tuong-Vi / Yao, Shihua / Wang, Yahong / Rolfe, Alan / Selvaraj, Anand / Darman, Rachel / Ke, Jiyuan / Warmuth, Markus / Smith, Peter G / Larsen, Nicholas A / Yu, Lihua / Zhu, Ping / Fekkes, Peter / Vaillancourt, Frédéric H / Bolduc, David M

The Journal of biological chemistry

2019 Volume 294, Issue 45, Page(s) 16966–16977

Abstract: DNMT3A (DNA methyltransferase 3A) is ... ...

Abstract	DNMT3A (DNA methyltransferase 3A) is a
MeSH term(s)	DNA/metabolism ; DNA (Cytosine-5-)-Methyltransferases/chemistry ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; Humans ; Models, Molecular ; Mutation ; Protein Multimerization ; Protein Structure, Quaternary
Chemical Substances	DNA (9007-49-2) ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA methyltransferase 3A (EC 2.1.1.37)
Language	English
Publishing date	2019-10-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA119.010126
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Article ; Online: Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket.

Cell chemical biology

2020 Volume 27, Issue 3, Page(s) 259–268.e5

Abstract: Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor ... ...

Abstract	Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor growth in some cancer types, while in others CPS1 activity prevents the buildup of toxic levels of intratumoral ammonia to allow for sustained tumor growth. Targeted CPS1 inhibitors may, therefore, provide a therapeutic benefit for cancer patients with tumors overexpressing CPS1. Herein, we describe the discovery of small-molecule CPS1 inhibitors that bind to a previously unknown allosteric pocket to block ATP hydrolysis in the first step of carbamoyl phosphate synthesis. CPS1 inhibitors are active in cellular assays, blocking both urea synthesis and CPS1 support of the pyrimidine biosynthetic pathway, while having no activity against CPS2. These newly discovered CPS1 inhibitors are a first step toward providing researchers with valuable tools for probing CPS1 cancer biology.
MeSH term(s)	Adenosine Triphosphate/antagonists & inhibitors ; Adenosine Triphosphate/metabolism ; Allosteric Regulation/drug effects ; Carbamoyl-Phosphate Synthase (Ammonia)/antagonists & inhibitors ; Carbamoyl-Phosphate Synthase (Ammonia)/genetics ; Carbamoyl-Phosphate Synthase (Ammonia)/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Hydrolysis/drug effects ; Models, Molecular ; Molecular Structure ; Piperidines/chemistry ; Piperidines/pharmacology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Thiazoles/chemistry ; Thiazoles/pharmacology
Chemical Substances	Enzyme Inhibitors ; H3B-120 ; Piperidines ; Small Molecule Libraries ; Thiazoles ; Adenosine Triphosphate (8L70Q75FXE) ; CPS1 protein, human (EC 6.3.4.16) ; Carbamoyl-Phosphate Synthase (Ammonia) (EC 6.3.4.16)
Language	English
Publishing date	2020-02-03
Publishing country	United States
Document type	Journal Article
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2020.01.009
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Article: Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3.

ACS medicinal chemistry letters

2020 Volume 12, Issue 1, Page(s) 93–98

Abstract: Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper ... ...

Abstract	Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties.
Language	English
Publishing date	2020-12-02
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.0c00517
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