Journal of Molecular Biology最新文献

{"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}

{"title":"Deciphering Plant-Microbe Symbioses: A Molecular Blueprint for Precision Agriculture","authors":"Ertao Wang","doi":"10.1016/j.jmb.2026.169668","DOIUrl":"10.1016/j.jmb.2026.169668","url":null,"abstract":"<div><div>Symbioses between plants and microbes such as mycorrhizal fungi and rhizobia, provide critical advantages in plant nutrient acquisition and stress resilience, and thereby underpin agricultural sustainability. However, plants coexist with a myriad of soil microbes, including mutualists, pathogens and commensals, and so must accurately differentiate between beneficial, detrimental, and neutral partners to optimize tradeoffs between growth and defense. Since 2013, our research group has been dedicated to addressing fundamental questions in plant–microbe symbioses. Our work encompasses the exchange of nutrients and signals between symbionts, and the plant discrimination between mutualistic and pathogenic microbes within the rhizosphere microbiome. We first discovered fatty acids as the main carbon source supplied by plants to arbuscular mycorrhizal (AM) fungi and later revealed the phosphate starvation response-centered regulatory network that controls the root and AM fungi phosphorus uptake pathways. In addition, we identified the receptors that recognize Myc factors and have made inroads on revealing the mechanisms underlying how plants distinguish symbiotic and immune signals. The legume-rhizobium symbiosis is understood to have evolved from AM symbiosis. Related to this, our group identified the Nod factor co-receptor, MtLICK1/2, and revealed that a SHR-SCR module specifies legume cortical cell fate to enable root nodulation. Collectively, our work has provided fundamental insights into the two most agriculturally important plant–microbe symbioses, thereby paving the way for innovative strategies that harness these interactions to advance sustainable agriculture.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 7","pages":"Article 169668"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099703","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":"Structural Comparison of the Human G93A Mutant SOD1 to the Wild-type SOD1 Filaments","authors":"Yeongjin Baek ,&nbsp;Hyojeong Lee ,&nbsp;Eun-Su Park ,&nbsp;Minho Park ,&nbsp;Yurim Wee ,&nbsp;Hyunmin Kim ,&nbsp;Soung-Hun Roh ,&nbsp;Nam-Chul Ha","doi":"10.1016/j.jmb.2026.169642","DOIUrl":"10.1016/j.jmb.2026.169642","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by Cu, Zn-superoxide dismutase (SOD1) misfolding and aggregation, particularly in familial cases. The G93A mutation in SOD1, strongly associated with familial ALS, is widely studied in transgenic mouse models of the disease. In this study, we investigated the filament structure of the G93A mutant SOD1 using cryo-electron microscopy. The resulting fibrils consisted of a single protofilament with a left-handed helical twist, closely resembling those formed by wild-type (WT) SOD1 under identical conditions. Self- and cross-seeding experiments promoted filament formation in both WT and G93A mutant SOD1, compared to the no-seed condition. Notably, the G93A mutant exhibited significantly higher susceptibility to proteolysis in its native state than WT SOD1. Mass spectrometry analysis suggested that the structurally disordered electrostatic loop acts as a key common intermediate structure in filament formation for both WT and G93A mutant SOD1. These findings suggest that shared filament formation pathways underlie the aggregation of both WT and G93A mutant SOD1, providing new insights into the molecular mechanisms contributing to ALS pathogenesis.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 6","pages":"Article 169642"},"PeriodicalIF":4.5,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016914","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":"The Structure of a Thermostable Phage’s Portal Vertex and Neck Complex Illuminates the Headful Maturation Mechanism","authors":"Emma L. Sedivy,&nbsp;Emily Agnello ,&nbsp;Julia E. Hobaugh,&nbsp;Rakeyah Ahsan,&nbsp;Kangkang Song ,&nbsp;Chen Xu,&nbsp;Brian A. Kelch","doi":"10.1016/j.jmb.2026.169641","DOIUrl":"10.1016/j.jmb.2026.169641","url":null,"abstract":"<div><div>Viruses assemble from component parts inside their host cells, but the mechanisms coordinating this complex process are not completely understood. In tailed bacteriophages, the genome is packaged into its capsid shell through the portal complex. The portal complex then closes to retain DNA and connects to the tail, which is required for host recognition and infection. The trigger to stop pumping DNA and assemble the mature virus has been a longstanding conundrum in the field. We determined the structure of the portal, the proteins that connect it to the tail, and portal vertex in the hyperthermophilic phage Oshimavirus using cryo-Electron Microscopy (cryo-EM). We find highly intertwined loop structures, like in a wicker basket, potentially stabilizing the portal vertex against high temperatures. Moreover, we observe that the portal protrudes from the capsid in mature virions. We propose that portal is repositioned by packaged DNA, forming a pressure-sensitive switch that terminates genome packaging and triggers tail attachment in headful phages.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 6","pages":"Article 169641"},"PeriodicalIF":4.5,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987641","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":"Structural Basis for Bacteriophage P22 Assembly and Infection Initiation","authors":"Chunyan Wang ,&nbsp;Huaxin Yu ,&nbsp;Taehyun Park ,&nbsp;Ian J. Molineux ,&nbsp;Jun Liu","doi":"10.1016/j.jmb.2026.169647","DOIUrl":"10.1016/j.jmb.2026.169647","url":null,"abstract":"<div><div><em>Salmonella</em> phage P22 deploys a highly coordinated tail machine to recognize hosts and initiate infection. Here, we present a cryo-EM structure of wild-type P22 that defines how the tail apparatus assembles onto the capsid and how they interface. Flexible loop residues on both the portal protein gp1 and the capsid protein gp5 undergo pronounced positional shifts and engage multiple partners to accommodate the C12–C5 symmetry mismatch at the portal-capsid interface. The portal protein gp1 forms a distinctive ∼15-nm barrel that projects deep into the capsid interior. Comparison with a mutant lacking the three internal E (ejection) proteins indicates that these proteins reside within the portal-tail lumen in a poorly ordered state, yet are essential for stabilizing the extended portal barrel. We further show how the hub protein gp10 orchestrates the assembly of four distinct particle isomers through its coordinated interactions with portal gp1, adaptor gp4, tailspike gp9, and needle gp26. Finally, cryo-electron tomography reveals that the gp10 hub acts as a structural foundation for the assembly of one E protein into an extracellular channel that breaches the cell surface, with other E proteins forming a genome-translocating <em>trans</em>-envelope conduit.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 6","pages":"Article 169647"},"PeriodicalIF":4.5,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016985","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":"Pioneers: Growing Together With Molecular Dynamics Simulation and NMR for Studying Biomacromolecules in China","authors":"Yunyu Shi","doi":"10.1016/j.jmb.2026.169648","DOIUrl":"10.1016/j.jmb.2026.169648","url":null,"abstract":"<div><div>I am a Professor of Biophysics at the University of Science and Technology of China (USTC). I graduated from the Department of Physics, USTC, majoring in Biophysics, in 1965. From 1965 to 1970, I worked as an assistant researcher at the Institute of Chinese Medicine. I joined USTC as an Assistant Professor in 1970 and became a visiting scholar in the Department of Physical Chemistry at the University of Roma from 1979 to1981. My studies on computational biology were mentored by Professor De Santis and supported by the Ministry of Education of China. My studies on bio-NMR were mentored by Professor F. Conti at University of Roma while I simultaneously studied at the CNRS Structural Chemistry Laboratory in Italy. I returned to USTC in 1981 and established a multidisciplinary research team.</div><div>In 1985 and 1990, I visited the Department of Physical Chemistry, University of Groningen in the Netherlands for six months, under the guidance of Professor H.J.C. Berendsen and Dr. W.F. Van Gunsteren to learn molecular dynamics (MD) simulation of protein and under the guidance of Professor R. Kaptein and Dr. R. Boelens to learn heteronuclear multidimensional NMR experiments for structure determination of proteins in solution. Our laboratory is the first research group to do MD simulation on protein in China and is also one of the pioneer laboratories using NMR to study protein structure in solution in China.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 6","pages":"Article 169648"},"PeriodicalIF":4.5,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027854","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":"Pioneers: Academic Career in Cryo-EM Structural Biology","authors":"Sen-Fang Sui","doi":"10.1016/j.jmb.2026.169649","DOIUrl":"10.1016/j.jmb.2026.169649","url":null,"abstract":"<div><div>I established my independent laboratory in 1989 at the Department of Biological Sciences and Biotechnology (which was renamed the School of Life Sciences in 2009) at Tsinghua University. Since 1991, I have held a professorship at Tsinghua University for more than three decades. My laboratory was one of the earliest in China to apply three-dimensional electron microscopy to the study of the structures of biological macromolecules. In the 1990s, my laboratory primarily focused on the two-dimensional crystallization of proteins on lipid monolayer and their structural studies using electron microscopy. By the late  1990s, our laboratory gradually shifted towards structural research using the single-particle electron microscopy technique. A representative achievement of this period was the elucidation of the transition of the protease DegP between a cage-like oligomer in solution and a bowl-shaped oligomer on membrane surfaces. Following the resolution revolution in cryo-electron microscopy, we determined the high-resolution structure of an 18-megadalton phycobilisome in 2017—marking the first near-atomic model of this giant complex since its discovery half a century ago. In recent years, we have focused on <em>in situ</em> high-resolution structure determination and method development. In 2023, we reported a near-atomic resolution <em>in situ</em> structure of the phycobilisome–photosystem membrane protein megacomplex,determined from cellular lamellae.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 6","pages":"Article 169649"},"PeriodicalIF":4.5,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027828","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}