Journal of Molecular Biology最新文献_第4页

SeqWord Motif Mapper: A Tool for Rapid Statistical Analysis and Visualization of Epigenetic Modifications in Bacterial Genomes SeqWord Motif Mapper：细菌基因组表观遗传修饰的快速统计分析和可视化工具。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-06-25 DOI: 10.1016/j.jmb.2025.169307

Christophe M.J. Lefebvre, Rian E. Pierneef, Oleg N. Reva

{"title":"SeqWord Motif Mapper: A Tool for Rapid Statistical Analysis and Visualization of Epigenetic Modifications in Bacterial Genomes","authors":"Christophe M.J. Lefebvre, Rian E. Pierneef, Oleg N. Reva","doi":"10.1016/j.jmb.2025.169307","DOIUrl":"10.1016/j.jmb.2025.169307","url":null,"abstract":"<div><div>Genomic methylation in bacteria plays a crucial role in gene regulation, chromosome replication, pathogenicity, and defense against phages. While single-molecule real-time (SMRT) sequencing technologies have advanced the detection of epigenetically modified bases, the statistical analysis of their distribution and the possible roles they play in bacterial cells remains challenging. To address this gap, we developed SeqWord Motif Mapper (SWMM), a computational tool designed for the statistical analysis and visualization of bacterial methylation patterns. SWMM utilizes PacBio sequencing data to identify sequence coverage, methylation motif distribution, and putative functional associations. Implemented in Python 3.9, the tool is platform-independent and requires minimal dependencies, making it accessible to a wide range of users. The SWMM command-line interface and a web-based version of the program facilitate the exploration of epigenetic modifications across bacterial genomes. Through case studies on different bacterial and archaeal taxa, we demonstrated that genome methylation in microorganisms extends beyond canonical sites and possibly influences gene expression, adaptation, and genome architecture. The tool enables detailed statistical evaluation of methylation motif distribution and provides insights into the potential regulatory roles of epigenetic modifications in bacterial genomes. SWMM is freely available at <span><span>https://begp.bi.up.ac.za</span><svg><path></path></svg></span>, with source code hosted on GitHub at <span><span>https://github.com/chrilef/BactEpiGenPro</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 19","pages":"Article 169307"},"PeriodicalIF":4.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511364","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

Formation Mechanism and Antibacterial Activity of Natural Antimicrobial Lysozyme with Antibiotics Doxycycline and Tigecycline 天然抗菌溶菌酶与多西环素、替加环素的形成机制及抑菌活性。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-06-25 DOI: 10.1016/j.jmb.2025.169304

Xiangrong Li , Xianfei Liu , Jingjing Zhao , Yujie Sun , Yuxin Liang , Qiongya Hu

{"title":"Formation Mechanism and Antibacterial Activity of Natural Antimicrobial Lysozyme with Antibiotics Doxycycline and Tigecycline","authors":"Xiangrong Li , Xianfei Liu , Jingjing Zhao , Yujie Sun , Yuxin Liang , Qiongya Hu","doi":"10.1016/j.jmb.2025.169304","DOIUrl":"10.1016/j.jmb.2025.169304","url":null,"abstract":"<div><div>The combination of lysozyme with antibiotics has emerged as a promising strategy to combat bacterial resistance; however, the lack of mechanistic understanding regarding their molecular-level interactions remains a critical knowledge gap, hindering the rational design of optimized synergistic therapies. Through integrated spectroscopic techniques (FTIR, CD, UV–vis, fluorescence), thermodynamic analyses, molecular docking, and 200-ns molecular dynamics simulation, we established that doxycycline/tigecycline bind lysozyme via moderate-affinity hydrophobic interactions (<em>K</em><sub>a</sub> ∼ 10<sup>4</sup> L mol<sup>−1</sup>) but with distinct binding patterns-tigecycline forms additional hydrogen bonds through its glycylamino side chain, yielding higher stability and lower free drug fraction (<em>f</em><sub>u</sub>) compare to doxycycline. Additionally, doxycycline and tigecycline have a relatively mild effect on lysozyme conformation, but doxycycline has a greater impact on lysozyme conformation than tigecycline. Key findings reveal a paradoxical efficacy relationship: while doxycycline exhibits stronger intrinsic antibacterial activity, the lysozyme-tigecycline complex demonstrates synergistic enhancement (particularly against <em>E. coli</em>) through stable binding-mediated protection and optimized release kinetics, whereas lysozyme-doxycycline’s weaker binding leads to premature release and reduced activity. These results fundamentally advance protein-drug interaction paradigms by demonstrating that optimal therapeutic outcomes require balanced binding stability, with broader implications for designing lysozyme-based delivery systems where moderately strong interactions enable synergistic effects while preserving structural integrity, offering a template for developing combination therapies against antimicrobial resistance.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 19","pages":"Article 169304"},"PeriodicalIF":4.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511362","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

Sequence and Structure-based Prediction of Allosteric Sites. 基于序列和结构的变构位点预测。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-06-24 DOI: 10.1016/j.jmb.2025.169305

Juan Xie, Gaoxiang Pan, Luhua Lai

引用次数: 0

Biomimetic, Peptide-guided Silica Formation by Real-time NMR of Elastin-like and R5 Fusion Peptides - Bimodal Peptide Aggregation Drives Dual-pathway Silicification Mechanisms. 弹性蛋白和R5融合肽的实时核磁共振仿生，肽引导二氧化硅形成-双峰肽聚集驱动双途径硅化机制。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-06-23 DOI: 10.1016/j.jmb.2025.169303

Dörte Brandis, Dominik Obrist, Martin F T Haßler, Dennis Kurzbach

{"title":"Biomimetic, Peptide-guided Silica Formation by Real-time NMR of Elastin-like and R5 Fusion Peptides - Bimodal Peptide Aggregation Drives Dual-pathway Silicification Mechanisms.","authors":"Dörte Brandis, Dominik Obrist, Martin F T Haßler, Dennis Kurzbach","doi":"10.1016/j.jmb.2025.169303","DOIUrl":"10.1016/j.jmb.2025.169303","url":null,"abstract":"<p><p>Biomimetic silica particles are promising materials for applications in drug delivery, enzyme encapsulation, and environmental technologies due to their intrinsic biocompatibility and eco-friendly nature. Often, these composites are formed via peptide self-assemblies that can scavenge silicate from solution under mild conditions, thus acting as templates for silica coatings. However, the molecular complexities and large sizes of the peptide assemblies, often exceeding megadaltons, pose significant challenges for structural and functional characterization, leaving key mechanistic aspects unresolved and often impeding rational materials design. Here, we aim to help overcome this bottleneck using methyl-detected Nuclear Magnetic Resonance (NMR) spectroscopy. We investigate a variant of the biotechnologically important R5 peptide, which can template the formation of highly defined silica nanoparticles with variable morphologies. In particular, we focus on elastin-like polypeptide (ELP)-R5 fusion constructs, which have recently been suggested as a promising drug delivery platform. The ELP tag allows for spontaneous self-assembly of R5 above a critical lower solution temperature without the need for any additives that trigger peptide condensation. Exploiting strong methyl resonance intensities and the suppression of the influence of spurious proton exchange on resonance line widths, we were able to access the ELP-R5 peptides within these assemblies. We could follow their resonances even throughout the nanoparticle formation event, simultaneously in real-time and at residue resolution. Integrating our NMR approach with scanning-electron microscopy and dynamic light scattering, we find a previously unrecognized bimodal size distribution of peptide aggregates, giving rise to dual silicification pathways with distinct kinetics.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169303"},"PeriodicalIF":4.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493299","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

NMR in the Age of Modern Biomedical Research and Drug Discovery. 核磁共振在现代生物医学研究和药物发现的时代。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-06-23 DOI: 10.1016/j.jmb.2025.169302

Xiuxiu Lu, Wazo Myint, Christine S Muli, Mioara Larion, Hiroshi Matsuo, Kylie J Walters

{"title":"NMR in the Age of Modern Biomedical Research and Drug Discovery.","authors":"Xiuxiu Lu, Wazo Myint, Christine S Muli, Mioara Larion, Hiroshi Matsuo, Kylie J Walters","doi":"10.1016/j.jmb.2025.169302","DOIUrl":"10.1016/j.jmb.2025.169302","url":null,"abstract":"<p><p>The success of artificial intelligence for structure prediction has led to forecasts of a reduced need for experimental structural biology. Here, we focus on nuclear magnetic resonance (NMR) spectroscopy and its various applications to biomedical research, including and extending beyond structural biology. As a structural tool, NMR is highly complementary to X-ray crystallography and cryo-electron microscopy (cryo-EM) and uniquely suited for studies of intrinsically disordered and dynamic systems in real time. It produces spectral fingerprints of biomolecules at the atomic scale to provide information on the structure, interactions, and motions that occur in solution. We focus on the power of NMR to characterize moderately sized dynamic systems, identify and validate the binding of small molecule ligands to biomolecular targets, and its capacity to further develop and be empowered by artificial intelligence-based structural prediction software. Experimental structural biology begins with sample preparation, and we present recent advancements for overcoming hurdles associated with reconstitution of biological systems for NMR studies and ongoing challenges, including in the application of NMR for cell-based research. NMR is aptly suited to bench-to-bedside efforts for its ability to do metabolomic profiling and follow drug response. We present the capacity of NMR to delve into complexities that are the foundation of biological function and focus on its ongoing challenges and opportunities to apply NMR for the advancement of biomedical research.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169302"},"PeriodicalIF":4.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493300","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

An Intrinsically Disordered Region of Histone Demethylase KDM5A Activates Catalysis Through Interactions With the Nucleosomal Acidic Patch and DNA 组蛋白去甲基化酶KDM5A的内在紊乱区域通过与核小体酸性斑块和DNA的相互作用激活催化。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-06-20 DOI: 10.1016/j.jmb.2025.169301

Ali M. Palla , Chien-Chu Lin , Michael J. Trnka , Emme M. Leao , Nektaria Petronikolou , Alma L. Burlingame , Robert K. McGinty , Danica Galonić Fujimori

{"title":"An Intrinsically Disordered Region of Histone Demethylase KDM5A Activates Catalysis Through Interactions With the Nucleosomal Acidic Patch and DNA","authors":"Ali M. Palla , Chien-Chu Lin , Michael J. Trnka , Emme M. Leao , Nektaria Petronikolou , Alma L. Burlingame , Robert K. McGinty , Danica Galonić Fujimori","doi":"10.1016/j.jmb.2025.169301","DOIUrl":"10.1016/j.jmb.2025.169301","url":null,"abstract":"<div><div>Lysine demethylase 5A (KDM5A) plays a key role in the regulation of chromatin accessibility by catalyzing the removal of trimethyl marks on histone H3K4 (H3K4me3). KDM5A is also an oncogenic driver, with overexpression of KDM5A observed in various cancers, including breast, lung, and ovarian cancer. Past studies have characterized the functions of KDM5A domains, including KDM5A interactions with the histone H3 tail, but have yet to identify the broader mechanisms that drive KDM5A binding to the nucleosome. Through investigation of binding and catalysis on nucleosome substrates, we uncovered multivalent interactions of KDM5A with the H2A/H2B acidic patch and DNA that play crucial roles in the regulation of catalytic activity. We also identified an intrinsically disordered region (IDR) containing bifunctional arginine-rich motifs capable of binding to both the histone H2A/H2B acidic patch and nucleosomal DNA that is necessary for catalysis on nucleosome substrates. Our findings both elucidate previously unknown mechanisms that regulate KDM5A catalytic activity and reveal the ability of an IDR to engage in multiple interactions with chromatin.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 19","pages":"Article 169301"},"PeriodicalIF":4.7,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367780","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

Autophagy Across Scales – From Molecules to Physiology 自噬跨越各个层面——从分子到生理。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-06-19 DOI: 10.1016/j.jmb.2025.169300

Helene Knævelsrud, Sharon A. Tooze

引用次数: 0

The Citrullinating Enzyme PADI4 Binds to Lipids: Identification of New Target Interactions for Cancer Therapy 瓜氨酸化酶PADI4与脂质结合：癌症治疗新靶标相互作用的鉴定。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-06-16 DOI: 10.1016/j.jmb.2025.169297

Salomé Araujo-Abad , Borja García-Peñarrubia , A.Marcela Giudici , José L. Neira , Bruno Rizzuti , Camino de Juan Romero , José A. Poveda

{"title":"The Citrullinating Enzyme PADI4 Binds to Lipids: Identification of New Target Interactions for Cancer Therapy","authors":"Salomé Araujo-Abad , Borja García-Peñarrubia , A.Marcela Giudici , José L. Neira , Bruno Rizzuti , Camino de Juan Romero , José A. Poveda","doi":"10.1016/j.jmb.2025.169297","DOIUrl":"10.1016/j.jmb.2025.169297","url":null,"abstract":"<div><div>Cancer cells need to implement and maintain molecular mechanisms relying on an energy trade-off between resistance and key functions to survive. Among them, changes in lipid metabolism are crucial. Phosphatidylserine (PS), phosphatidylcholine (PC) and phosphatidic acid (PA) are some of the lipids forming cell membranes and having key functions in lipid metabolism. PADI4 is an enzyme implicated in the conversion of arginine to citrulline (citrullination), that has been related with the development of several types of cancers. In this work, we report the lipid binding properties of PADI4. Such binding was assayed <em>in vitro</em> against zwitterionic (PC) and anionic (PA and PS) lipids, and it was monitored by several biophysical techniques. Furthermore, results <em>in silico</em> showed that the binding of PADI4 with PA, PC and PS occurred at the active site of the enzyme. This binding was confirmed <em>in cellulo</em> by using PS as the target lipid, employing immunofluorescence (IF) and proximity ligation assay (PLA) in different cancer cell lines. The use <em>in cellulo</em> of a specific enzymatic inhibitor of PADI4, GSK484, abolished the binding between PADI4 and PS in cancer cells, further indicating that their interaction occurred at the protein active site. Altogether, this work shows that PADI4 was capable of binding to lipids, and opens the venue to study the role that it could be playing in deimination processes and cancer development. Moreover, this study lays the foundation for developing novel cancer therapies from new perspectives, based on the interaction of lipids with citrullinating enzymes.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169297"},"PeriodicalIF":4.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324080","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

ATP as a Key Modulator of Fused-in-sarcoma Phase Separation and Aggregation: Insights into Amyotrophic Lateral Sclerosis Pathogenesis ATP作为融合肉瘤相分离和聚集的关键调节剂：对肌萎缩性侧索硬化症发病机制的见解。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-06-16 DOI: 10.1016/j.jmb.2025.169295

Keiji Kitamura , Itta Tsukui , Fuka Sasaki , Yutaro Shiramasa , Miyu Arayama , Manato Morishita , Ayano Oshima , Soichiro Kitazawa , Tomoshi Kameda , Ryo Kitahara

{"title":"ATP as a Key Modulator of Fused-in-sarcoma Phase Separation and Aggregation: Insights into Amyotrophic Lateral Sclerosis Pathogenesis","authors":"Keiji Kitamura , Itta Tsukui , Fuka Sasaki , Yutaro Shiramasa , Miyu Arayama , Manato Morishita , Ayano Oshima , Soichiro Kitazawa , Tomoshi Kameda , Ryo Kitahara","doi":"10.1016/j.jmb.2025.169295","DOIUrl":"10.1016/j.jmb.2025.169295","url":null,"abstract":"<div><div>Fused in sarcoma (FUS) is an RNA-binding protein, the aberrant aggregation of which is linked to amyotrophic lateral sclerosis (ALS). Liquid–liquid phase separation (LLPS) of FUS facilitates functional condensate formation and can drive pathological aggregation under certain conditions. The aggregation-inhibitory effects of ATP, a key cellular hydrotrope, have been reported for multiple proteins; however, how ATP, present at approximately 1–12 mM concentrations in cells, regulates LLPS and amyloid fibril formation remains unclear. Therefore, we investigated how ATP modulates the LLPS behavior and aggregation of FUS and its ALS-linked variants, R495X and P525L. ATP destabilized both normal LLPS and aberrant high-pressure LLPS (HP-LLPS), with a relatively strong inhibitory effect on HP-LLPS. Pressure-jump experiments demonstrated that ATP reduced the irreversible aggregation propensity of HP-LLPS, particularly in ALS variants that exhibited enhanced aggregation compared to that by wild-type FUS. Molecular dynamic simulations further revealed that the triphosphate and adenosine moieties of ATP synergistically disrupted intermolecular interactions that were crucial for phase separation, leveraging its amphipathic properties. Notably, ATP concentrations within the physiological range (1–12 mM) significantly inhibited FUS aggregation, suggesting a protective role in cellular environments. These results indicate that decreased intracellular ATP levels may exacerbate aberrant phase transitions of FUS, contributing to ALS onset. This study underscores the potential of ATP as a therapeutic modulator of protein phase separation and aggregation, providing valuable insights into the molecular mechanisms of ALS. Our findings open new avenues for targeting ATP-regulated pathways for treating neurodegenerative disorders.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 17","pages":"Article 169295"},"PeriodicalIF":4.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293154","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

The C-terminal Tail of Ubiquitin-Specific Protease 7 Facilitates Ubiquitin Release and Ensures Efficient Catalytic Turnover 泛素特异性蛋白酶7的c端尾部促进泛素释放并确保有效的催化转换。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-06-16 DOI: 10.1016/j.jmb.2025.169298

Emilie J. Korchak, Dane H. Geddes-Buehre, Irina Bezsonova

引用次数: 0