Nucleic Acids Research最新文献_第8页

Use of a small molecule microarray screen to identify inhibitors of the catalytic RNA subunit of Methanobrevibacter smithii RNase P. 利用小分子芯片筛选确定 Smithii Methanobrevibacter RNase P 催化 RNA 亚基的抑制剂。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-01-07 DOI: 10.1093/nar/gkae1190

Vaishnavi Sidharthan, Christopher D Sibley, Kara Dunne-Dombrink, Mo Yang, Walter J Zahurancik, Sumirtha Balaratnam, Damien B Wilburn, John S Schneekloth, Venkat Gopalan

{"title":"Use of a small molecule microarray screen to identify inhibitors of the catalytic RNA subunit of Methanobrevibacter smithii RNase P.","authors":"Vaishnavi Sidharthan, Christopher D Sibley, Kara Dunne-Dombrink, Mo Yang, Walter J Zahurancik, Sumirtha Balaratnam, Damien B Wilburn, John S Schneekloth, Venkat Gopalan","doi":"10.1093/nar/gkae1190","DOIUrl":"10.1093/nar/gkae1190","url":null,"abstract":"Despite interest in developing therapeutics that leverage binding pockets in structured RNAs-whose dysregulation leads to diseases-such drug discovery efforts are limited. Here, we have used a small molecule microarray (SMM) screen to find inhibitors of a large ribozyme: the Methanobrevibacter smithii RNase P RNA (Msm RPR, ∼300 nt). The ribonucleoprotein form of RNase P, which catalyzes the 5'-maturation of precursor tRNAs, is a suitable drug target as it is essential, structurally diverse across life domains, and present in low copy. From an SMM screen of 7,300 compounds followed by selectivity profiling, we identified 48 hits that bound specifically to the Msm RPR-the catalytic subunit in Msm (archaeal) RNase P. When we tested these hits in precursor-tRNA cleavage assays, we discovered that the drug-like M1, a diaryl-piperidine, inhibits Msm RPR (KI, 17 ± 1 μM) but not a structurally related archaeal RPR, and binds to Msm RPR with a KD(app) of 8 ± 3 μM. Structure-activity relationship analyses performed with synthesized analogs pinpointed groups in M1 that are important for its ability to inhibit Msm RPR. Overall, the SMM method offers prospects for advancing RNA druggability by identifying new privileged scaffolds/chemotypes that bind large, structured RNAs.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

tRNA thiolation optimizes appressorium-mediated infection by enhancing codon-specific translation in Magnaporthe oryzae tRNA硫代化通过增强稻瘟病菌密码子特异性翻译优化了附着子介导的感染

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-01-07 DOI: 10.1093/nar/gkae1302

Xinrong Zhang, Rongrong He, Yinan Li, Shuchao Ren, Shikun Xiang, Jing Zheng, Zhiguang Qu, Shu Zhou, Zhipeng Zhou, Xiao-Lin Chen

引用次数: 0

High hydrostatic pressure promotes gene transcription via a cystathionine-β-synthase domain-containing protein in the hyperthermophilic archaeon Pyrococcus yayanosii 高静水压力通过含半胱硫氨酸-β-合成酶结构域的蛋白在嗜热古球菌雅氏焦球菌中促进基因转录

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-01-07 DOI: 10.1093/nar/gkae1289

Cong Li, Siyuan Li, Qinghao Song, Lin-tai Da, Jun Xu

{"title":"High hydrostatic pressure promotes gene transcription via a cystathionine-β-synthase domain-containing protein in the hyperthermophilic archaeon Pyrococcus yayanosii","authors":"Cong Li, Siyuan Li, Qinghao Song, Lin-tai Da, Jun Xu","doi":"10.1093/nar/gkae1289","DOIUrl":"https://doi.org/10.1093/nar/gkae1289","url":null,"abstract":"Cystathionine-β-synthase (CBS) domains are ubiquitously prevalent in all kingdoms of life. Remarkably, in archaea, proteins consisting of solely CBS domains are widespread. However, the biological functions of CBS proteins in archaea are still unknown. Here, we identified a high hydrostatic pressure regulator (HhpR) that comprises four CBS domains serving as a transcriptional activator via specifically binding to the UAS (upstream activating sequence) motif situated within the promoter region of an operon in a hyperthermophilic archaeon Pyrococcus yayanosii under high hydrostatic pressure (HHP). By combining molecular dynamics simulations, in vitro and in vivo assays, we revealed the potential binding interfaces between HhpR and its specific DNA binding site. Particularly, one stem–loop region in HhpR (termed as ‘Arm’) was found to play a critical role in regulating the transcription activity, and the 192 position in the Arm region is an essential site in dictating the conformational changes of HhpR at HHP condition. Our work provides novel insights into the structure–function relationship of CBS-containing proteins that participate in archaeal gene regulation as general transcriptional activators.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"8 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design and in vitr o anticancer assessment of a click chemistry-derived dinuclear copper artificial metallo-nuclease 化学衍生双核铜人工金属核酸酶的设计及体外抗癌评价

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-01-07 DOI: 10.1093/nar/gkae1250

Simon Poole, Obed Akwasi Aning, Vickie McKee, Thomas Catley, Aaraby Yoheswaran Nielsen, Helge Thisgaard, Pegah Johansson, Georgia Menounou, Joseph Hennessy, Creina Slator, Alex Gibney, Alice Pyne, Bríonna McGorman, Fredrik Westerlund, Andrew Kellett

{"title":"Design and in vitr o anticancer assessment of a click chemistry-derived dinuclear copper artificial metallo-nuclease","authors":"Simon Poole, Obed Akwasi Aning, Vickie McKee, Thomas Catley, Aaraby Yoheswaran Nielsen, Helge Thisgaard, Pegah Johansson, Georgia Menounou, Joseph Hennessy, Creina Slator, Alex Gibney, Alice Pyne, Bríonna McGorman, Fredrik Westerlund, Andrew Kellett","doi":"10.1093/nar/gkae1250","DOIUrl":"https://doi.org/10.1093/nar/gkae1250","url":null,"abstract":"Copper compounds with artificial metallo-nuclease (AMN) activity are mechanistically unique compared to established metallodrugs. Here, we describe the development of a new dinuclear copper AMN, Cu2-BPL-C6 (BPL-C6 = bis-1,10-phenanthroline-carbon-6), prepared using click chemistry that demonstrates site-specific DNA recognition with low micromolar cleavage activity. The BPL-C6 ligand was designed to force two redox-active copper centres—central for enhancing AMN activity—to bind DNA, via two phenanthroline ligands separated by an aliphatic linker. DNA-binding experiments, involving circular dichroism spectroscopy, agarose gel electrophoresis and fluorescence quenching, revealed a preference for binding with adenine-thymine-rich DNA. The oxidative cleavage mechanism of Cu2-BPL-C6 was then elucidated using in vitro molecular and biophysical assays, including in-liquid atomic force microscopy analysis, revealing potent DNA cleavage mediated via superoxide and hydrogen peroxide oxidative pathways. Single-molecule analysis with peripheral blood mononuclear cells identified upregulated single-strand DNA lesions in Cu2-BPL-C6-treated cells. Using specific base excision repair (BER) enzymes, we showed that Endo IV selectively repairs these lesions indicating that the complex generates apurinic and apyrimidinic adducts. Broad spectrum anticancer evaluation of BPL-C6 was performed by the National Cancer Institute’s 60 human cell line screen (NCI-60) and revealed selectivity for certain melanoma, breast, colon and non-small cell lung cancer cell lines.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"48 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to 'Accelerated discovery and miniaturization of novel single-stranded cytidine deaminases'. 更正“加速发现和小型化新型单链胞苷脱氨酶”。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-01-07 DOI: 10.1093/nar/gkae1287

引用次数: 0

Unveiling the unusual i-motif-derived architecture of a DNA aptamer exhibiting high affinity for influenza A virus 揭示了对甲型流感病毒具有高亲和力的DNA适体的不同寻常的i基序衍生结构

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-01-07 DOI: 10.1093/nar/gkae1282

Vladimir Tsvetkov, Bartomeu Mir, Rugiya Alieva, Alexander Arutyunyan, Ilya Oleynikov, Roman Novikov, Elizaveta Boravleva, Polina Kamzeeva, Timofei Zatsepin, Andrey Aralov, Carlos González, Elena Zavyalova

{"title":"Unveiling the unusual i-motif-derived architecture of a DNA aptamer exhibiting high affinity for influenza A virus","authors":"Vladimir Tsvetkov, Bartomeu Mir, Rugiya Alieva, Alexander Arutyunyan, Ilya Oleynikov, Roman Novikov, Elizaveta Boravleva, Polina Kamzeeva, Timofei Zatsepin, Andrey Aralov, Carlos González, Elena Zavyalova","doi":"10.1093/nar/gkae1282","DOIUrl":"https://doi.org/10.1093/nar/gkae1282","url":null,"abstract":"Non-canonical nucleic acid structures play significant roles in cellular processes through selective interactions with proteins. While both natural and artificial G-quadruplexes have been extensively studied, the functions of i-motifs remain less understood. This study investigates the artificial aptamer BV42, which binds strongly to influenza A virus hemagglutinin and unexpectedly retains its i-motif structure even at neutral pH. However, BV42 conformational heterogeneity hinders detailed structural analysis. Molecular dynamics simulations and chemical modifications of BV42 helped us to identify a potential binding site, allowing for aptamer redesign to eliminate the conformational diversity while retaining binding affinity. Nuclear magnetic resonance spectroscopy confirmed the i-motif/duplex junction with the three-cytosine loop nearby. This study highlights the unique structural features of the functional i-motif and its role in molecular recognition of the target.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"72 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanistic insights into Sindbis virus infection: noncapped genomic RNAs enhance the translation of capped genomic RNAs to promote viral infectivity. Sindbis病毒感染的机制洞察：非帽盖基因组rna增强了帽盖基因组rna的翻译，从而促进了病毒的感染性。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-01-07 DOI: 10.1093/nar/gkae1230

Deepa Karki, Autumn T LaPointe, Cierra Isom, Milton Thomas, Kevin J Sokoloski

{"title":"Mechanistic insights into Sindbis virus infection: noncapped genomic RNAs enhance the translation of capped genomic RNAs to promote viral infectivity.","authors":"Deepa Karki, Autumn T LaPointe, Cierra Isom, Milton Thomas, Kevin J Sokoloski","doi":"10.1093/nar/gkae1230","DOIUrl":"10.1093/nar/gkae1230","url":null,"abstract":"Alphaviruses are globally distributed, vector-borne RNA viruses with high outbreak potential and no clinical interventions, posing a significant global health threat. Previously, the production and packaging of both viral capped and noncapped genomic RNAs (cgRNA and ncgRNA) during infection was reported. Studies have linked ncgRNA production to viral infectivity and pathogenesis, but its precise role remains unclear. To define the benefits of ncgRNAs, pure populations of capped and noncapped Sindbis virus (SINV) gRNAs were synthesized and transfected into host cells. The data showed that mixtures of cgRNAs and ncgRNAs had higher infectivity compared to pure cgRNAs, with mixtures containing low cgRNA proportions exceeding linear infectivity expectations. This enhancement depended on co-delivery of cgRNAs and ncgRNAs to the same cell and required the noncapped RNAs to be viral in origin. Contrary to the initial hypothesis that the ncgRNAs serve as replication templates, the cgRNAs were preferentially replicated. Further analysis revealed that viral gene expression, viral RNA (vRNA) synthesis and particle production were enhanced in the presence of ncgRNAs, which function to promote cgRNA translation early in infection. Our findings highlight the importance of ncgRNAs in alphaviral infection, showing they enhance cgRNA functions and significantly contribute to viral infectivity.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to 'The Pfam protein families database: embracing AI/ML'. 更正“Pfam蛋白质家族数据库：拥抱AI/ML”。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-01-07 DOI: 10.1093/nar/gkae1276

引用次数: 0

Deciphering ligand and metal ion dependent intricate folding landscape of Vc2 c-di-GMP riboswitch aptamer 破译配体和金属离子依赖的Vc2 c-di-GMP核开关适配体的复杂折叠景观

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-01-07 DOI: 10.1093/nar/gkae1296

Ji-Yeon Shin, Seo-Ree Choi, So Young An, Kyeong-Mi Bang, Hyun Kyu Song, Jeong-Yong Suh, Nak-Kyoon Kim

{"title":"Deciphering ligand and metal ion dependent intricate folding landscape of Vc2 c-di-GMP riboswitch aptamer","authors":"Ji-Yeon Shin, Seo-Ree Choi, So Young An, Kyeong-Mi Bang, Hyun Kyu Song, Jeong-Yong Suh, Nak-Kyoon Kim","doi":"10.1093/nar/gkae1296","DOIUrl":"https://doi.org/10.1093/nar/gkae1296","url":null,"abstract":"Riboswitches are RNAs that recognize ligands and regulate gene expression. They are typically located in the untranslated region of bacterial messenger RNA and consist of an aptamer and an expression platform. In this study, we examine the folding pathway of the Vc2 (Vibrio cholerae) riboswitch aptamer domain, which targets the bacterial secondary messenger cyclic-di-GMP. We demonstrated by nuclear magnetic resonance (NMR) and isothermal titration calorimetry that the stable folding of the Vc2 riboswitch requires an adequate supply of Mg2+, Na+ and K+ ions. We found that Mg2+ has a crucial role in the pre-folding of the aptamer, while K+ is essential for establishing the long-range G-C interactions and stabilizing the ligand binding pocket. Precise imino proton assignments revealed the progressive folding of the aptamer. The results indicate that the P2 helix consists of weaker and more dynamic base pairs compared to the P1b helix, allowing the rearrangement of the base pairs in the P2 helix during the folding process required for effective ligand recognition. This study provides a profound understanding riboswitch architecture and dynamics at the atomic level under physiological conditions as well as structural information on apo-state RNA.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"14 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to 'Circular oligomeric particles formed by Ros/MucR family members mediate DNA organization in α-proteobacteria'. 更正“由Ros/MucR家族成员形成的环状寡聚颗粒介导α-变形菌的DNA组织”。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-01-07 DOI: 10.1093/nar/gkae1269

引用次数: 0