Journal of Molecular Biology最新文献

{"title":"The Anticancer Drug Mitoxantrone Triggers the Formation of Ribosome-enriched Stress Granules Independently of the Classical Translational Control Pathways","authors":"Marta Leśniczak-Staszak ,&nbsp;Paulina Pietras ,&nbsp;Agnieszka Fedoruk-Wyszomirska ,&nbsp;Martino Morici ,&nbsp;Mateusz Sowiński ,&nbsp;Szymon Krawczyk ,&nbsp;Małgorzata Andrzejewska ,&nbsp;Eliza Wyszko ,&nbsp;Michał Nowicki ,&nbsp;Paul J. Anderson ,&nbsp;Ewelina Gowin ,&nbsp;Pavel Ivanov ,&nbsp;Daniel N. Wilson ,&nbsp;Witold Szaflarski","doi":"10.1016/j.jmb.2026.169671","DOIUrl":"10.1016/j.jmb.2026.169671","url":null,"abstract":"<div><div>Mitoxantrone (MIT) is a chemotherapeutic drug widely used for its DNA intercalation and inhibition of topoisomerase. In this work, we show that MIT also affects cytoplasmic RNA–ribosome organization. In human cancer cells, MIT induced stress granules (SGs) that contained large ribosomal subunit proteins, including eL8, together with polyadenylated mRNA. These MIT-induced SGs were different from arsenite-induced SGs: they formed without eIF2α phosphorylation, mTOR inhibition, or 4E-BP1 activity, and they remained stable in the presence of cycloheximide and after drug withdrawal. In vitro assays further demonstrated that MIT promotes ribosome aggregation in a concentration- and salt-dependent manner. Taken together, our results identify a distinct type of ribosome-enriched SGs that form through RNA–ribosome condensation rather than classical translational stress pathways. This mechanism provides a direct example of how a clinically used drug can reorganize cytoplasmic RNA–protein complexes, with possible consequences for mRNA regulation, cancer therapy, and neurodegenerative disease.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169671"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117274","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}

{"title":"Rising Star: Combining Bioinformatics and Experimental Biology to Decoding Non-coding RNAs and RNA Modifications","authors":"Xiu-Jie Wang","doi":"10.1016/j.jmb.2026.169684","DOIUrl":"10.1016/j.jmb.2026.169684","url":null,"abstract":"<div><div>Xiu-Jie Wang studied biochemistry as a master student at Hong Kong University of Sciences and Technology, and obtained her PhD degree in bioinformatics from The Rockefeller University, then joint Institute of Genetics and Developmental Biology, Chinese Academy of Sciences to establish her own research group. The major research focus of Xiu-Jie Wang’s group is to identify functional non-coding RNAs, especially microRNAs, through the combination of bioinformatics and experimental approaches. They found many microRNAs involving in essential physiological processes in plants, virus, and mouse embryonic stem cells, and uncovered a novel function of microRNAs in regulating m⁶A RNA modification. These findings subsequently led them to extend their research towards m⁶A regulation and its role in long-term memory formation. Xiu-Jie Wang’s group also developed several bioinformatics tools and databases, which have served as useful resources for the research community.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169684"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163266","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}

{"title":"Oligomerization-Dependent Regulation of LrhA Controls Bacterial Flagellar Biosynthesis","authors":"Baichun Niu,&nbsp;Masahide Kikkawa,&nbsp;Xuguang Jiang","doi":"10.1016/j.jmb.2026.169682","DOIUrl":"10.1016/j.jmb.2026.169682","url":null,"abstract":"<div><div>LysR-type transcriptional regulators (LTTRs) are a diverse family of proteins that regulate various cellular processes, including motility in bacteria. In <em>Escherichia coli</em>, the LTTR LrhA represses flagellar biosynthesis by inhibiting the <em>flhDC</em> operon. However, the structural basis underlying this regulation has remained unclear. Here, we determined both a high-resolution crystal structure and a cryo-EM reconstruction of LrhA, revealing a predominant and stable tetrameric organization with pronounced structural variability in its effector-binding region. Structural and biochemical analyses demonstrate that mutations in these variable regions perturb the oligomeric equilibrium of LrhA, shifting the balance between tetrameric and dimeric species. This shift correlates with enhanced DNA binding affinity and stronger repression of the <em>flhDC</em> promoter. While ligand binding may similarly modulate LrhA activity, our data primarily support a model in which alterations in oligomeric state mediated by the variable regions regulate LrhA function. Together, these findings provide a structural framework for understanding how LrhA controls bacterial motility and offer broader insights into oligomerization-based regulation within the LTTR family.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169682"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140736","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}

{"title":"Rising Stars: In vivo Monitoring of Neurochemical Dynamics by Genetically Encoded Neuromodulator Sensors","authors":"Shengwei Fu ,&nbsp;Yulong Li","doi":"10.1016/j.jmb.2026.169669","DOIUrl":"10.1016/j.jmb.2026.169669","url":null,"abstract":"<div><div>Dr. Yulong Li received his undergraduate education in biophysics and physiology at Peking University, and subsequently completed his Ph.D. training under the mentorship of Dr. George J. Augustine at Duke University, where he investigated fundamental mechanisms of synaptic transmission. He then pursued postdoctoral research in the laboratory of Dr. Richard W. Tsien at Stanford University, where he began developing genetically encoded indicators for applications in neuroscience.</div><div>Since 2012, Dr. Yulong Li established his lab at Peking University. His research has been at the forefront of developing the genetically encoded fluorescent sensors for neurotransmitters and neuromodulators, which have emerged as powerful tools for real-time monitoring of the dynamic changes of these molecules with high sensitivity, selectivity, spatiotemporal resolution, and minimal invasiveness <em>in vivo</em>. This article provides a comprehensive overview of the design strategies and key progress in this rapid evolving field, emphasizing how these tools have transformed the study of neuromodulation.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169669"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099499","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}

{"title":"Rising Stars: Molecular Mechanisms of Ligand Recognition and Functional Modulation of GPCRs","authors":"Shuo Han ,&nbsp;Qiuxiang Tan ,&nbsp;Shuling Lin ,&nbsp;Kun Chen ,&nbsp;Maozhou He ,&nbsp;Qiang Zhao ,&nbsp;Beili Wu","doi":"10.1016/j.jmb.2026.169674","DOIUrl":"10.1016/j.jmb.2026.169674","url":null,"abstract":"<div><div>In response to a variety of signals outside of cells, G protein-coupled receptors (GPCRs) play essential roles in cell signal transduction by relaying the extracellular signals to the intracellular side through various signaling mechanisms, which govern diverse physiological and pathological processes. These receptors are involved in many diseases and comprise the largest drug target family. However, the molecular mechanisms underlying the GPCR signal transduction are poorly understood, which hinders the drug discovery with only a small portion of receptors having drugs marketed. Over the past decade, our laboratory has been focused on the ligand recognition and functional modulation mechanisms of different GPCRs, aiming for better understanding of the physiology and pathology of this receptor superfamily and new clues to carry out drug development. Through extensive structural and functional studies, we uncovered diverse interaction patterns of GPCRs in recognizing various ligands, including small molecules, peptides, and proteins. These molecular details not only reveal key factors that define ligand selectivity and receptor specificity, but also provide insights into allosteric modulation, ligand promiscuity, and intrinsic activation. Our knowledge about the GPCR modulations were further extended by investigating the conformational rearrangements and dynamics of GPCRs upon activation and coupling to downstream signaling transducers. With different molecular architectures, different receptors exhibit distinct patterns in regulating their activities and abilities to stimulate various signaling pathways, which are key for understanding biased signaling. These findings demonstrate the diversity and complexity of GPCR signaling and would enable development of novel drugs with improved efficacy and reduced side effects.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169674"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130784","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}

{"title":"Rising Star: Single Cell Omics Technologies: When Whole Omics Analysis Meets Single Cell Resolution","authors":"Fuchou Tang","doi":"10.1016/j.jmb.2026.169670","DOIUrl":"10.1016/j.jmb.2026.169670","url":null,"abstract":"<div><div>I got my PhD degree under the supervision of Prof. Kegang Shang in 2003. And I did my postdoc research in Azim Surani’s lab. Then I set up my own lab in Biomedical Pioneering Innovation Center at Peking University in 2010. My research has focused on developing single-cell omics sequencing technologies and employing these powerful tools to dissect the gene regulation networks in human germline cell development under both physiological and pathological conditions. My lab systematically developed a serial of single-cell omics sequencing technologies, including the first single-cell DNA methylome sequencing technology in 2013, which was considered to pioneer the single-cell epigenome field. In recent years, my lab has focused on developing single-cell omics long-read sequencing technologies based on single-molecule sequencing platforms, which can reveal critical features of the repetitive elements. The repetitive elements are considered as ‘dark matter’, which account for over half of our genome and play important roles for both normal development and numerous diseases. The research in my lab revealed critical features of the epigenetic reprogramming of human germline cells, deepening our understanding of these cells, which are fundamental to the transgenerational immortality of the human species.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169670"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099733","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}

{"title":"Rising Star: Exploring Weak Biomolecular Interactions: My Steady and Evolving Journey","authors":"Pilong Li","doi":"10.1016/j.jmb.2026.169680","DOIUrl":"10.1016/j.jmb.2026.169680","url":null,"abstract":"<div><div>This manuscript reflects the early stages of my ongoing journey into weak biomolecular interactions, beginning with my study of Vav1, a guanine nucleotide exchange factor. In this initial work, I uncovered how weak intramolecular interactions regulate protein activation, providing critical insights into their role in cellular processes like signal transduction. However, my understanding of weak interactions took an unexpected turn during research on the Nck/NWASP complex, when we serendipitously discovered that weak, multivalent interactions drive liquid–liquid phase separation (LLPS), a process essential for cellular organization. This unanticipated finding led to the development of the CoPIC platform, which enables high-throughput detection of weak interactions within living cells. Though the studies on Vav1 and LLPS are independent, both underscore the profound role of weak interactions in regulating cellular dynamics. This ongoing journey continues to challenge and deepen my understanding of how weak interactions orchestrate the complexity of biological systems. This personal trajectory exemplifies how pursuing seemingly focused mechanistic questions can unexpectedly reveal broader principles—here, that weak interactions are not peripheral but central architects of cellular complexity and adaptability.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169680"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140774","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}

{"title":"Rising Star: G Protein-coupled Receptors (GPCRs) in Microenvironment Pharmacology and Sensory Perception Pharmacology","authors":"Jia-Le Wang ,&nbsp;Shen-Ming Huang ,&nbsp;Nai-Kang Rong ,&nbsp;Shu-Hua Zhou ,&nbsp;Yi Sun ,&nbsp;Jin-Peng Sun","doi":"10.1016/j.jmb.2026.169679","DOIUrl":"10.1016/j.jmb.2026.169679","url":null,"abstract":"<div><div>Professor Jinpeng Sun has long been dedicated to pharmacological research on G protein-coupled receptors (GPCRs), achieving systematic advances in areas such as ligand–receptor recognition, drug target validation, and membrane receptor-based drug development. In 2007, he earned his Ph.D. in Molecular Pharmacology from the Albert Einstein College of Medicine, after which he conducted postdoctoral research in the laboratory of Nobel Laureate Professor Robert J. Lefkowitz at Duke University, a pioneering figure in GPCR biology. In 2011, Professor Sun established his independent research group in China, where he has since pursued in-depth investigations into GPCR pharmacology. To address key bottlenecks in GPCR drug discovery, such as the unclear pathophysiological hubs of complex diseases and the difficulty in designing selective drugs, Professor Sun’s team proposed that the dynamic and multiple interactions among ligands, receptors, and intracellular (membrane) effectors are important players in microenvironment establishment and adjustment that drive or modulate disease progresses. Based on this conceptual framework, they developed a suite of innovative methodologies, including endogenous ligand capture technology, highly sensitive multipathway GPCR activity profiling systems, and microscale force activation platforms. Using these tools, the team successfully identified membrane receptors for several critical hormones and metabolites, such as glucocorticoids, androgens, progesterone, and ceramides, resolving several long-standing questions in pharmacology. They were the first to discover the GPCR responsible for the sense of balance and elucidated the molecular mechanisms through which GPCRs sense mechanical force, odors, pruritic stimuli, and acidic or alkaline environments, substantially expanding the known functional scope of GPCR biology. Furthermore, by integrating chemical biology with signaling assays, Professor Sun’s group introduced theoretical models such as the “flute model” of functional coding of GPCR phosphorylation and “proline regions docking and sorting” for GPCR biased signaling. Exploiting AI-guided ligand design, Sun’s group developed over 20 selective lead compounds targeting the GPCRs involved in psychiatric, metabolic, cardiovascular, and aging-related disorders. Several candidates have completed preliminary pharmacokinetic and toxicity studies, demonstrating strong translational potential. This article systematically summarizes the key scientific contributions from Professor Sun Jinpeng’s laboratory over the past decade, highlighting their impact on receptor-ligand paring, signaling mechanism elucidation, tool development, and rational drug design, and discusses their implications for the future of precision medicine.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169679"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140691","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}

{"title":"Crystal Structure of PH0140: Exogenous Amino Acids Induce Open Octameric Assembly Enables PromoterTTTT Binding for Transcription Regulation","authors":"Richard Mariadasse ,&nbsp;Mohammed Ahmad ,&nbsp;Ravi Kant Pal ,&nbsp;Kohila Gurunathan ,&nbsp;Sneha Subramaniyan ,&nbsp;Bichitra K. Biswal ,&nbsp;Suresh Kumar Muthuvel ,&nbsp;Stalin Thambusamy ,&nbsp;Jeyakanthan Jeyaraman","doi":"10.1016/j.jmb.2026.169664","DOIUrl":"10.1016/j.jmb.2026.169664","url":null,"abstract":"<div><div>PH0140, a hypothetical protein from the Feast/Famine Regulatory Protein (FFRP) family in <em>Pyrococcus horikoshii OT3</em>, is predicted to play a role in transcriptional regulation in response to exogenous amino acids. Previous <em>in-silico</em> studies suggest that PH0140 has a binding preference for exogenous tryptophan and regulates transcription through DNA recognition and allostery. However, its structure and regulatory mechanism remain largely unexplored. In this study, we determined the crystal structure of PH0140 at a resolution of 2.0 Å, revealing that it binds to exogenous isoleucine through distinct structural features: a unique C-terminal loop region near the Effector-Binding Domain (EBD) and a β-strand (β2) with notable structural deviations from homologous proteins. Size-exclusion chromatography showed that PH0140 forms oligomers in the presence of exogenous isoleucine and tryptophan. Furthermore, the amino acids binding were characterized through isothermal titration calorimetry (ITC). Studies suggest that exogenous tryptophan has a better binding affinity than isoleucine. To explore the structural basis of this ligand effect, we modeled an octameric PH0140–DNA complex containing a 111-bp promoter fragment and performed multiple molecular dynamics simulations. The simulations revealed that the octameric assembly undergoes a conformational opening to interact with the DNA promoter^TTTT region. The hydrophobic driven force on the EBD results in distortion of β-strand (β4) into loop (Chain G) to adopt an open conformation, which facilitates interaction with the promoter^TTTT region for transcription regulation.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169664"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111935","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}

{"title":"CEP290 is Associated With Chromatin Accessibility of Hepatitis B virus cccDNA","authors":"Sadahiro Iwabuchi ,&nbsp;Yiang-Yi Li ,&nbsp;Takeharu Sakamoto ,&nbsp;Tadashi Imafuku ,&nbsp;Kazuhisa Murai ,&nbsp;Atsushi Tajima ,&nbsp;Masao Honda ,&nbsp;Shinichi Hashimoto","doi":"10.1016/j.jmb.2026.169700","DOIUrl":"10.1016/j.jmb.2026.169700","url":null,"abstract":"<div><div>Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) serves as a stable nuclear template for viral transcription, yet the mechanisms controlling its chromatin accessibility remain poorly understood. Here, we performed single-cell assay for transposase-accessible chromatin sequencing (ATAC-seq) in HBV-infected human hepatocytes to profile cccDNA chromatin states. We identified discrete closed regions within cccDNA, while a subset of cells exhibited open chromatin at these loci, accompanied by elevated <em>CEP290</em> (centrosomal protein 290) and several additional genes. Functional studies using CRISPR/Cas9-mediated knockdown or CRISPR-based transcriptional activation demonstrated that <em>CEP290</em> positively regulates cccDNA and total HBV DNA levels. Combining <em>CEP290</em> knockdown with entecavir or HBV-targeting siRNA further reduced cccDNA, although complete elimination was not achieved. Bulk ATAC-seq demonstrated that <em>CEP290</em> influences chromatin accessibility at selected cccDNA regions and affects host genomic loci. Taken together, our findings suggest that <em>CEP290</em>, along with other gene candidates identified from regions of sporadically opened cccDNA chromatin, may influence HBV cccDNA regulation and viral replication. These results illustrate that single-cell chromatin profiling can reveal host factors potentially involved in HBV persistence.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169700"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177168","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}