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Article ; Online: Role of Monovalent Ions in the NKCC1 Inhibition Mechanism Revealed through Molecular Simulations.

Janoš, Pavel / Magistrato, Alessandra

International journal of molecular sciences

2022 Volume 23, Issue 23

Abstract: The secondary active Na-K-Cl cotransporter 1 (NKCC1) promotes electroneutral uptake of two chloride ions, one sodium ion and one potassium ion. NKCC1 regulates ... ...

Abstract	The secondary active Na-K-Cl cotransporter 1 (NKCC1) promotes electroneutral uptake of two chloride ions, one sodium ion and one potassium ion. NKCC1 regulates Cl
MeSH term(s)	Animals ; Humans ; Zebrafish/metabolism ; Bumetanide/pharmacology ; Solute Carrier Family 12, Member 2 ; Potassium/metabolism ; Sodium/metabolism ; Chlorides/metabolism ; K Cl- Cotransporters
Chemical Substances	Bumetanide (0Y2S3XUQ5H) ; Solute Carrier Family 12, Member 2 ; Potassium (RWP5GA015D) ; Sodium (9NEZ333N27) ; Chlorides
Language	English
Publishing date	2022-12-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232315439
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Assessing the Binding Mode of a Splicing Modulator Stimulating Pre-mRNA Binding to the Plastic U2AF2 Splicing Factor.

Rozza, Riccardo / Janoš, Pavel / Magistrato, Alessandra

Journal of chemical information and modeling

2023 Volume 63, Issue 23, Page(s) 7508–7517

Abstract: RNA recognition motifs (RRMs) play a pivotal role in RNA metabolism and the regulation of gene expression. Owing to their plasticity and fuzziness, targeting RRM/RNA interfaces with small molecules is a daunting challenge for drug discovery campaigns. ... ...

Abstract	RNA recognition motifs (RRMs) play a pivotal role in RNA metabolism and the regulation of gene expression. Owing to their plasticity and fuzziness, targeting RRM/RNA interfaces with small molecules is a daunting challenge for drug discovery campaigns. The U2AF2 splicing factor, which recognizes the polypyrimidine (polyPy) sequence of premature messenger (pre-m)RNA, exhibits a dynamic architecture consisting of two RRMs joined by a disordered linker. An inhibitor, NSC-194308, was shown to enhance the binding of pre-mRNA to U2AF2, selectively triggering cell death in leukemia cell lines containing spliceosome mutations. The NSC-194308 binding mode remains elusive; yet, unraveling its knowledge may offer intriguing insights for effectively targeting U2AF2 and other flexible protein/protein/RNA interfaces with small molecules. To infer plausible NSC-194308 binding poses to U2AF2, here, we applied and benchmarked the performance of static and dynamic docking approaches, elucidating the molecular basis of the NSC-194308-induced pre-mRNA stabilization on U2AF2. We demonstrate that introducing dynamic effects is mandatory to assess the binding mode of the inhibitors when they target plastic and modular architectures, such as those formed by interacting RRMs. The latter are widespread across RNA binding proteins; therefore, this mechanism may be broadly applicable to discover new therapeutics aimed at selectively modulating the RNA function by targeting protein/protein/RNA interfaces.
MeSH term(s)	RNA Precursors/genetics ; RNA Precursors/metabolism ; RNA Splicing Factors/genetics ; RNA Splicing Factors/metabolism ; RNA Splicing ; RNA/metabolism ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism
Chemical Substances	RNA Precursors ; RNA Splicing Factors ; RNA (63231-63-0) ; RNA-Binding Proteins
Language	English
Publishing date	2023-11-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.3c01204
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Article ; Online: Cancer-Related Mutations Alter RNA-Driven Functional Cross-Talk Underlying Premature-Messenger RNA Recognition by Splicing Factor SF3b.

Spinello, Angelo / Janos, Pavel / Rozza, Riccardo / Magistrato, Alessandra

The journal of physical chemistry letters

2023 Volume 14, Issue 27, Page(s) 6263–6269

Abstract: The pillar of faithful premature-messenger (pre-mRNA) splicing is the precise recognition of key intronic sequences by specific splicing factors. The heptameric splicing factor 3b (SF3b) recognizes the branch point sequence (BPS), a key part of the 3' ... ...

Abstract	The pillar of faithful premature-messenger (pre-mRNA) splicing is the precise recognition of key intronic sequences by specific splicing factors. The heptameric splicing factor 3b (SF3b) recognizes the branch point sequence (BPS), a key part of the 3' splice site. SF3b contains SF3B1, a protein holding recurrent cancer-associated mutations. Among these, K700E, the most-frequent SF3B1 mutation, triggers aberrant splicing, being primarily implicated in hematologic malignancies. Yet, K700E and the BPS recognition site are 60 Å apart, suggesting the existence of an allosteric cross-talk between the two distal spots. Here, we couple molecular dynamics simulations and dynamical network theory analysis to unlock the molecular terms underpinning the impact of SF3b splicing factor mutations on pre-mRNA selection. We establish that by weakening and remodeling interactions of pre-mRNA with SF3b, K700E scrambles RNA-mediated allosteric cross-talk between the BPS and the mutation site. We propose that the altered allostery contributes to cancer-associated missplicing by mutated SF3B1. This finding broadens our comprehension of the elaborate mechanisms underlying pre-mRNA metabolism in eukaryotes.
MeSH term(s)	Humans ; RNA Splicing Factors/genetics ; RNA Splicing Factors/metabolism ; RNA, Messenger ; RNA Precursors/genetics ; RNA Precursors/metabolism ; RNA ; Mutation ; Neoplasms/genetics ; Transcription Factors
Chemical Substances	RNA Splicing Factors ; RNA, Messenger ; RNA Precursors ; RNA (63231-63-0) ; Transcription Factors
Language	English
Publishing date	2023-07-03
Publishing country	United States
Document type	Journal Article
ISSN	1948-7185
ISSN (online)	1948-7185
DOI	10.1021/acs.jpclett.3c01402
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Article ; Online: Monovalent Ionic Atmosphere Modulates the Selection of Suboptimal RNA Sequences by Splicing Factors' RNA Recognition Motifs.

Rozza, Riccardo / Janoš, Pavel / Magistrato, Alessandra

Journal of chemical information and modeling

2023 Volume 63, Issue 10, Page(s) 3086–3093

Abstract: The U2AF2 splicing factor is involved in the RNA recognition of the pre-mRNA poly-pyrimidine signaling sequence. This protein contains two RRM domains connected by a flexible linker, which ensure the preferential selection of a poly-uridine sequence over ...

Abstract	The U2AF2 splicing factor is involved in the RNA recognition of the pre-mRNA poly-pyrimidine signaling sequence. This protein contains two RRM domains connected by a flexible linker, which ensure the preferential selection of a poly-uridine sequence over a poly-cytosine one. In this work, all-atom simulations provide insights into the U2AF2 recognition mechanism and on the features underlying its selectivity. Our outcomes show that U2AF2's RNA recognition is driven by cooperative events modulated by RNA-protein and RNA-ion interactions. Stunningly, monovalent ions contribute to mediating the binding of the weakly binding polyC strand, thus contributing to the selection of suboptimal poly-pyrimidine tracts. This finding broadens our understanding of the diverse traits tuning splicing factors' selectivity and adaptability to precisely handle and process diverse pre-mRNA sequences.
MeSH term(s)	RNA/chemistry ; RNA Precursors/genetics ; RNA Precursors/chemistry ; RNA Precursors/metabolism ; RNA Splicing Factors/metabolism ; Base Sequence ; RNA Recognition Motif ; Pyrimidines
Chemical Substances	RNA (63231-63-0) ; RNA Precursors ; RNA Splicing Factors ; Pyrimidines
Language	English
Publishing date	2023-05-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.3c00110
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Article ; Online: All-Atom Simulations Uncover the Molecular Terms of the NKCC1 Transport Mechanism.

Janoš, Pavel / Magistrato, Alessandra

Journal of chemical information and modeling

2021 Volume 61, Issue 7, Page(s) 3649–3658

Abstract: The secondary-active Na-K-Cl cotransporter 1 (NKCC1), member of the cation-chloride cotransporter (CCC) family, ensures the electroneutral movement of ... ...

Abstract	The secondary-active Na-K-Cl cotransporter 1 (NKCC1), member of the cation-chloride cotransporter (CCC) family, ensures the electroneutral movement of Cl
MeSH term(s)	Biological Transport ; Humans ; Ion Transport ; Sodium/metabolism ; Solute Carrier Family 12, Member 2/metabolism ; Symporters ; K Cl- Cotransporters
Chemical Substances	SLC12A2 protein, human ; Solute Carrier Family 12, Member 2 ; Symporters ; Sodium (9NEZ333N27)
Language	English
Publishing date	2021-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.1c00551
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Article ; Online: The conformational plasticity of the selectivity filter methionines controls the in-cell Cu(I) uptake through the CTR1 transporter.

Janoš, Pavel / Aupič, Jana / Ruthstein, Sharon / Magistrato, Alessandra

QRB discovery

2022 Volume 3, Page(s) e3

Abstract: Copper is a trace element vital to many cellular functions. Yet its abnormal levels are toxic to cells, provoking a variety of severe diseases. The high affinity copper transporter 1 (CTR1), being the main in-cell copper [Cu(I)] entry route, tightly ... ...

Abstract	Copper is a trace element vital to many cellular functions. Yet its abnormal levels are toxic to cells, provoking a variety of severe diseases. The high affinity copper transporter 1 (CTR1), being the main in-cell copper [Cu(I)] entry route, tightly regulates its cellular uptake via a still elusive mechanism. Here, all-atoms simulations unlock the molecular terms of Cu(I) transport in eukaryotes disclosing that the two methionine (Met) triads, forming the selectivity filter, play an unprecedented dual role both enabling selective Cu(I) transport and regulating its uptake rate thanks to an intimate coupling between the conformational plasticity of their bulky side chains and the number of bound Cu(I) ions. Namely, the Met residues act as a gate reducing the Cu(I) import rate when two ions simultaneously bind to CTR1. This may represent an elegant autoregulatory mechanism through which CTR1 protects the cells from excessively high, and hence toxic, in-cell Cu(I) levels. Overall, our outcomes resolve fundamental questions in CTR1 biology and open new windows of opportunity to tackle diseases associated with an imbalanced copper uptake.
Language	English
Publishing date	2022-04-21
Publishing country	England
Document type	Journal Article
ISSN	2633-2892
ISSN (online)	2633-2892
DOI	10.1017/qrd.2022.2
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Article ; Online: Intrinsically disordered ectodomain modulates ion permeation through a metal transporter.

Aupič, Jana / Lapenta, Fabio / Janoš, Pavel / Magistrato, Alessandra

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 48, Page(s) e2214602119

Abstract: The function of many channels and transporters is enriched by the conformational plasticity of intrinsically disordered regions (IDRs). Copper transporter 1 (Ctr1) is the main entry point for Cu(I) ions in eukaryotes and contains IDRs both at its N- ... ...

Abstract	The function of many channels and transporters is enriched by the conformational plasticity of intrinsically disordered regions (IDRs). Copper transporter 1 (Ctr1) is the main entry point for Cu(I) ions in eukaryotes and contains IDRs both at its N-terminal (Nterm) and C-terminal ends. The former delivers copper ions from the extracellular matrix to the selectivity filter in the Ctr1 lumen. However, the molecular mechanism of this process remains elusive due to Nterm's disordered nature. Here, we combine advanced molecular dynamics simulations and circular dichroism experiments to show that Cu(I) ions and a lipidic environment drive the insertion of the Nterm into the Ctr1 selectivity filter, causing its opening. Through a lipid-aided conformational switch of one of the transmembrane helices, the conformational change of the selectivity filter propagates down to the cytosolic gate of Ctr1. Taken together, our results elucidate how conformational variability of IDRs modulates ion transport.
MeSH term(s)	Ions ; Copper ; Ion Transport ; Molecular Dynamics Simulation
Chemical Substances	Ions ; Copper (789U1901C5)
Language	English
Publishing date	2022-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2214602119
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Article ; Online: Role of computational and structural biology in the development of small-molecule modulators of the spliceosome.

Rozza, Riccardo / Janoš, Pavel / Spinello, Angelo / Magistrato, Alessandra

Expert opinion on drug discovery

2022 Volume 17, Issue 10, Page(s) 1095–1109

Abstract: Introduction: RNA splicing is a pivotal step of eukaryotic gene expression during which the introns are excised from the precursor (pre-)RNA and the exons are joined together to form mature RNA products (i.e a protein-coding mRNA or long non-coding (lnc) ...

Abstract	Introduction: RNA splicing is a pivotal step of eukaryotic gene expression during which the introns are excised from the precursor (pre-)RNA and the exons are joined together to form mature RNA products (i.e a protein-coding mRNA or long non-coding (lnc)RNAs). The spliceosome, a complex ribonucleoprotein machine, performs pre-RNA splicing with extreme precision. Deregulated splicing is linked to cancer, genetic, and neurodegenerative diseases. Hence, the discovery of small-molecules targeting core spliceosome components represents an appealing therapeutic opportunity. Area covered: Several atomic-level structures of the spliceosome and distinct splicing-modulators bound to its protein/RNA components have been solved. Here, we review recent advances in the discovery of small-molecule splicing-modulators, discuss opportunities and challenges for their therapeutic applicability, and showcase how structural data and/or all-atom simulations can illuminate key facets of their mechanism, thus contributing to future drug-discovery campaigns. Expert opinion: This review highlights the potential of modulating pre-RNA splicing with small-molecules, and anticipates how the synergy of computer and wet-lab experiments will enrich our understanding of splicing regulation/deregulation mechanisms. This information will aid future structure-based drug-discovery efforts aimed to expand the currently limited portfolio of selective splicing-modulators.
MeSH term(s)	Humans ; Introns ; RNA Precursors/chemistry ; RNA Precursors/genetics ; RNA Precursors/metabolism ; RNA Splicing ; Spliceosomes/chemistry ; Spliceosomes/genetics ; Spliceosomes/metabolism
Chemical Substances	RNA Precursors
Language	English
Publishing date	2022-08-24
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	2259618-5
ISSN	1746-045X ; 1746-0441
ISSN (online)	1746-045X
ISSN	1746-0441
DOI	10.1080/17460441.2022.2114452
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Article ; Online: All-Atom Simulations Elucidate the Impact of U2AF2 Cancer-Associated Mutations on Pre-mRNA Recognition.

Rozza, Riccardo / Saltalamacchia, Andrea / Orrico, Clarissa / Janoš, Pavel / Magistrato, Alessandra

Journal of chemical information and modeling

2022

Abstract: The U2AF2 splicing factor, made of two tandem RNA recognition motifs (RRMs) joined by a flexible linker, selects the intronic polypyrimidine sequence of premature mRNA, thus ensuring splicing fidelity. Increasing evidence links mutations of key splicing ... ...

Abstract	The U2AF2 splicing factor, made of two tandem RNA recognition motifs (RRMs) joined by a flexible linker, selects the intronic polypyrimidine sequence of premature mRNA, thus ensuring splicing fidelity. Increasing evidence links mutations of key splicing factors, including U2AF2, to a variety of cancers. Nevertheless, the impact of U2AF2 cancer-associated mutations on polypyrimidine recognition remains unclear. Here, we combined extensive (18 μs-long) all-atom molecular dynamics simulations and dynamical network theory analysis (NWA) of U2AF2, in its wild-type form and in the presence of the six most frequent cancer-associated mutations, bound to a poly-U strand. Our results reveal that the selected mutations affect the pre-mRNA binding at two hot spot regions, irrespectively of where these mutants are placed on the distinct U2AF2 domains. Complementarily, NWA traced the existence of cross-communication pathways, connecting each mutation site to these recognition hot spots, whose strength is altered by the mutations. Our outcomes suggest the existence of a structural/dynamical interplay of the two U2AF2's RRMs underlying the recognition of the polypyrimidine tract and reveal that the cancer-associated mutations affect the polypyrimidine selection by altering the RRMs' cooperativity. This mechanism may be shared by other RNA binding proteins hallmarked, like U2AF2, by multidomain architecture and high plasticity.
Language	English
Publishing date	2022-08-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.2c00511
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Article: Amidoxime-functionalized bead cellulose for the decomposition of highly toxic organophosphates

Janoš, Pavel / Tokar, Oldřich / Došek, Marek / Mazanec, Karel / Ryšánek, Petr / Kormunda, Martin / Henych, Jiří / Janoš, Pavel

RSC advances. 2021 May 18, v. 11, no. 29

2021

Abstract: Regenerated bead cellulose is a promising material with excellent mechanical and rheological properties, ideally suited for advanced environmental applications. By introducing the amidoxime functional group into the glucose unit at the C-6 position, ... ...

Abstract	Regenerated bead cellulose is a promising material with excellent mechanical and rheological properties, ideally suited for advanced environmental applications. By introducing the amidoxime functional group into the glucose unit at the C-6 position, highly effective reactive sorbent was prepared and used to destroy priority hazardous substances such as organophosphate pesticides or nerve-paralytic chemical warfare agents (CWAs). Quantum mechanical (QM) calculations were performed to study the interactions of organophosphates with amidoxime functional groups at the molecular level. It was found that the energetic reaction barrier of the rate-limiting step is markedly reduced (from 31.40 to 11.37 kcal mol⁻¹) in the case of the amidoxime-catalysed degradation of parathion methyl, which resulted in a dramatic increase in the degradation rate; this was fully confirmed by experiments, in which the pesticide degradation proceeded at the time scale of several hours (t₁/₂ = 20–30 hours at pH 7.22).
Keywords	cellulose ; glucose ; pH ; parathion-methyl ; pesticide degradation ; quantum mechanics ; reaction kinetics ; sorbents ; toxicity
Language	English
Dates of publication	2021-0518
Size	p. 17976-17984.
Publishing place	The Royal Society of Chemistry
Document type	Article
Note	NAL-AP-2-clean
ISSN	2046-2069
DOI	10.1039/d1ra01125a
Database	NAL-Catalogue (AGRICOLA)

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