Journal of Molecular Biology最新文献_第6页

Rising Star: Folding Pattern and Working Mechanism of Functional RNA Molecules 新星：功能性RNA分子的折叠模式和工作机制。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2026-01-08 DOI: 10.1016/j.jmb.2026.169635

Aiming Ren

{"title":"Rising Star: Folding Pattern and Working Mechanism of Functional RNA Molecules","authors":"Aiming Ren","doi":"10.1016/j.jmb.2026.169635","DOIUrl":"10.1016/j.jmb.2026.169635","url":null,"abstract":"<div><div><strong>Aiming Ren</strong> obtained her Ph.D. in Structural Biology and Chemical Biology from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and conducted postdoctoral research at the Memorial Sloan Kettering Cancer Center, where she investigated RNA molecules involved in gene expression regulation (riboswitches) and self-cleavage catalysis (ribozymes). Ren later established her independent laboratory at Zhejiang University, focusing on the structural and mechanistic understanding of functional RNAs—particularly riboswitches, self-cleaving ribozymes, and RNA fluorogenic aptamers (FLAP). These RNA molecules represent elegant examples of RNA nature’s regulatory, catalytic, and fluorescence activation strategies, performing precise chemical transformations and sophisticated functional control through dynamic structural rearrangements. The Ren laboratory combines biochemical and molecular biological approaches with high-resolution structural techniques, including X-ray crystallography and cryo-electron microscopy, to elucidate how RNA architectures encode regulatory, catalytic, and activation functions. Through systematic investigations, Ren and her team have explored how riboswitches couple ligand recognition to gene regulation via dynamic conformational shifts, uncovered the catalytic mechanisms of several newly discovered self-cleaving ribozymes, revealing both shared structural principles and unique chemical strategies underlying RNA self-scission. The group also investigated how RNA aptamers fold to stabilize the bound dyes and enhance their fluorescence by several thousand-fold. By bridging RNA chemistry, structure, and dynamics, Aiming Ren’s research aims to illuminate the fundamental principles governing RNA function and evolution. Her work provides deep insights into RNA-based regulation, catalysis, and fluorescence activation, offering important implications for understanding ancient biochemical systems and for the development of novel RNA-based tools and therapeutics.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169635"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948274","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

Microscale Thermophoresis for Thermodynamic Analysis: A Proof-of-Concept Study on LIMK Inhibitors 用于热力学分析的微尺度热电泳：LIMK抑制剂的概念验证研究。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2026-01-04 DOI: 10.1016/j.jmb.2025.169621

Solweig Chartier , Bérengère Claude , Rouba Nasreddine , Pierre Soule , Alexandra Launay , Mélanie Rapeto , Elodie Villalonga-Rosso , Béatrice Vallée , Muriel Sebban , Gaël Coadou , Reine Nehmé

{"title":"Microscale Thermophoresis for Thermodynamic Analysis: A Proof-of-Concept Study on LIMK Inhibitors","authors":"Solweig Chartier , Bérengère Claude , Rouba Nasreddine , Pierre Soule , Alexandra Launay , Mélanie Rapeto , Elodie Villalonga-Rosso , Béatrice Vallée , Muriel Sebban , Gaël Coadou , Reine Nehmé","doi":"10.1016/j.jmb.2025.169621","DOIUrl":"10.1016/j.jmb.2025.169621","url":null,"abstract":"<div><div>LIMK1 and LIMK2, key regulators of cytoskeleton dynamics, are notoriously difficult to produce and purify in quantities sufficient for conventional biochemical studies, yet they are promising therapeutic targets due to their role in actin filament turnover and microtubule remodeling. To overcome these limitations, we developed a microscale thermophoresis (MST)-based thermodynamic assay as a proof-of-concept to study LIMK–inhibitor interactions directly in HEK293 cell lysates overexpressing fluorescent miRFP670-LIMK fusion proteins, completely bypassing protein purification.</div><div>Dissociation constants (<em>K<sub>d</sub></em>) were measured across multiple temperatures and analyzed by van’t Hoff plots, yielding highly linear correlations (<em>r</em><sup>2</sup> = 0.958–0.999). LIMK1 and its kinase domain (Kin1) showed comparable binding behavior to TH-257 and LX7101 (Δ<em>G</em><sub>37°C</sub> = –10.3 ± 0.4 kcal mol<sup>−1</sup>), whereas LIMK2 interactions were significantly weaker (Δ<em>G</em><sub>37°C</sub> lower by ∼1.5 kcal mol<sup>−1</sup>). Binding was enthalpy-driven, with entropy opposing complex formation, highlighting opportunities for rational optimization of inhibitors.</div><div>This work establishes MST as a user-friendly, purification-free platform for deriving protein–ligand thermodynamics directly in cell lysates, providing a versatile proof-of-concept approach for studying challenging targets and guiding the development of therapeutically relevant inhibitors.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169621"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145909854","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

Metastable Folding of Bacillus subtilis glmS Ribozyme Modulates Turnover by RNase J1 枯草芽孢杆菌glmS核酶亚稳态折叠通过RNase J1调控周转。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-12-23 DOI: 10.1016/j.jmb.2025.169612

Yuan Lou , Sarah A. Woodson

引用次数: 0

Contributions of Local Structural and Energetic Features of DNA to Large-scale Genomic Organization DNA的局部结构和能量特征对大规模基因组组织的贡献。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-08-11 DOI: 10.1016/j.jmb.2025.169385

Wilma K. Olson , Nicolas Clauvelin , Stefjord Todolli , Xiang-Jun Lu

引用次数: 0

Evolution and design shape protein dynamics in LOV domains – spanning picoseconds to days 进化和设计形状蛋白质动力学在LOV结构域-跨越皮秒到天。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-12-18 DOI: 10.1016/j.jmb.2025.169599

Raoul E. Herzog, Isabelle F. Harvey-Seutcheu, Philipp Janke, Wenzhao Dai, Paul M. Fischer, Peter Hamm, Philipp J. Heckmeier

{"title":"Evolution and design shape protein dynamics in LOV domains – spanning picoseconds to days","authors":"Raoul E. Herzog, Isabelle F. Harvey-Seutcheu, Philipp Janke, Wenzhao Dai, Paul M. Fischer, Peter Hamm, Philipp J. Heckmeier","doi":"10.1016/j.jmb.2025.169599","DOIUrl":"10.1016/j.jmb.2025.169599","url":null,"abstract":"<div><div>Light-sensitive proteins allow organisms to perceive and respond to their environment, and have diversified over billions of years. Among these, Light-Oxygen-Voltage (LOV) domains are widespread photosensors that control diverse physiological processes and are increasingly used in optogenetics. Yet, the evolutionary constraints that shaped their protein dynamics and thereby their functional diversity remain poorly resolved. Here we systematically characterize the dynamics of 21 natural LOV core domains, significantly extending the spectroscopically resolved catalog through the addition of 18 previously unstudied variants. Using time-resolved spectroscopy, we uncover an exceptional kinetic diversity spanning from picoseconds to days and identify distinct functional clusters within the LOV family. These clusters reflect evolutionary branching, including a divergence of <span><math><mrow><mo>≈</mo></mrow></math></span>1.0 billion years between investigatedLOV variants from plants and <span><math><mrow><mo>≈</mo></mrow></math></span>0.4 billion years of separation within one of these functional clusters. Individual variants with extreme photocycles emerge as promising anchor points for optogenetic applications, ranging from highly efficient adduct formation to ultrafast recovery. Beyond natural diversity, we introduce a LOV domain generated by artificial intelligence-guided protein design. Despite being sequentially remote from its maternal template, this variant retains core photocycle function while exhibiting unique biophysical properties, thereby occupying a new region on the biophysical landscape. Our work emphasizes how billions of years of evolution defined LOV protein dynamics, and how protein design can expand this repertoire, engineering next-generation optogenetic tools.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169599"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800341","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

A Survey of Predicted Protein–Protein Interactions Involving Disordered Regions in Humans 一项涉及人类无序区域的预测蛋白质-蛋白质相互作用的调查。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2026-01-07 DOI: 10.1016/j.jmb.2026.169636

Jimin Pei, Jing Zhang, Qian Cong

{"title":"A Survey of Predicted Protein–Protein Interactions Involving Disordered Regions in Humans","authors":"Jimin Pei, Jing Zhang, Qian Cong","doi":"10.1016/j.jmb.2026.169636","DOIUrl":"10.1016/j.jmb.2026.169636","url":null,"abstract":"<div><div>Intrinsically disordered regions (IDRs) in proteins play a pivotal role in protein–protein interactions (PPIs). Using AlphaFold2 and enriched multiple sequence alignments, we predicted and investigated PPIs across the human proteome, focusing on those involving disordered regions. Our predictions show that disordered regions predominantly interact with ordered domains, whereas predicted disordered–disordered interactions are relatively rare. Although disordered regions typically lack annotated domains, certain regions—such as the keratin type II head domain and the Krüppel-associated box (KRAB)—mediate specific interactions. In contrast, their predicted binding partners frequently feature diverse Pfam domains, including protein kinase, WD40 repeat, and nuclear hormone receptor domains. These domains are enriched in nuclear localization and α-helical repeat motifs. Disordered regions involved in predicted PPIs exhibit higher sequence conservation than non-interacting disordered regions, suggesting evolutionary constraints at interaction interfaces. Moreover, certain posttranslational modifications (e.g., phosphorylation and acetylation) in disordered regions are enriched within predicted interaction interfaces, likely modulating binding affinities. Notably, we identified a significant enrichment of disease-associated mutations in predicted PPI interfaces involving disordered regions, underscoring their functional and pathological relevance. Together, these findings highlight the intricate interplay between disordered and ordered regions in mediating PPIs and provide insights into their structural and functional contributions to human health and disease.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169636"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941994","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

Structure of Two Tandem-Repeat Galectin Proteins Binding a Model Glycolipid Membrane 两个串联重复凝集素蛋白结合模型糖脂膜的结构。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2026-01-14 DOI: 10.1016/j.jmb.2026.169638

William R.K. Talley , Daniel Bazan , Jaroslaw Majewski , Herbert Kaltner , Crystal M. Vander Zanden

{"title":"Structure of Two Tandem-Repeat Galectin Proteins Binding a Model Glycolipid Membrane","authors":"William R.K. Talley , Daniel Bazan , Jaroslaw Majewski , Herbert Kaltner , Crystal M. Vander Zanden","doi":"10.1016/j.jmb.2026.169638","DOIUrl":"10.1016/j.jmb.2026.169638","url":null,"abstract":"<div><div>Tandem-repeat galectins are a family of proteins containing two carbohydrate recognition domains (CRDs) with affinity to various glycoproteins and glycolipids involved in cell signaling. Galectin-4 is expressed in intestinal epithelial cells, and galectin-8 is essential in regulating cell adhesion and immune response. Misregulation of both tandem-repeat galectins is linked to variable cancer cell behavior. Structure models for the membrane-bound forms of galectin-4 and galectin-8 were constructed from X-ray reflectivity measurements coupled with molecular dynamics for galectin-4. The proteins were bound to lipid monolayers containing their respective ligands, gangliosides GM1 or GM3, to determine the membrane-bound structure. Galectin-4 contains two CRDs with weak affinity for GM1, and it bound with both CRDs arranged near the membrane while dynamically sampling alternative conformations. Galectin-8, in contrast, contains only one CRD with tight binding to GM3, and one CRD was pointed towards the membrane while the other oriented away from the membrane. Shortening the peptide linker between the CRDs altered protein binding to the membrane, suggesting the linker likely facilitates stabilizing contacts between the CRDs. Overall, this work helps to illustrate the conformational dynamics of tandem-repeat galectins, emphasizing the roles of ligand affinity, linker peptide dynamics, and contacts between CRDs.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169638"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987685","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

Corrigendum to “E6 Proteins from Diverse Papillomaviruses Self-Associate Both In Vitro and In Vivo” [J. Mol. Biol. 396(1) (2010) 90–104] “不同乳头瘤病毒的E6蛋白在体外和体内的自我结合”的修正[J]。生物化学学报，2011,31(1)(2010):90-104。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2026-01-20 DOI: 10.1016/j.jmb.2026.169637

Katia Zanier , Christine Ruhlmann , Frederic Melin , Murielle Masson , Abdellahi Ould M’hamed Ould Sidi , Xavier Bernard , Benoit Fischer , Laurent Brino , Tutik Ristriani , Vladimir Rybin , Mireille Baltzinger , Scott Vande Pol , Petra Hellwig , Patrick Schultz , Gilles Travé

引用次数: 0

Bacterial Chemoreceptors Transmit Stimulus Signals Through Coupled Entropic Switches 细菌化学感受器通过耦合熵开关传递刺激信号。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-12-23 DOI: 10.1016/j.jmb.2025.169614

Caralyn E. Flack, John S. Parkinson

{"title":"Bacterial Chemoreceptors Transmit Stimulus Signals Through Coupled Entropic Switches","authors":"Caralyn E. Flack, John S. Parkinson","doi":"10.1016/j.jmb.2025.169614","DOIUrl":"10.1016/j.jmb.2025.169614","url":null,"abstract":"<div><div>Tracking ligand-induced conformational changes through transmembrane sensory proteins remains a challenge in signal transduction research. Our study followed propagation of stimulus signals through a bacterial transmembrane chemoreceptor (Tsr) that controls a cytoplasmic signaling kinase (CheA). We marked relay elements in the ∼200-Å long cytoplasmic four-helix bundle signaling domain with amino acid replacements that locked Tsr in kinase-ON or -OFF output and characterized the mutant receptors with <em>in vivo</em> assays that monitored Tsr structure (crosslinking) and function (kinase control). We found that conformational changes emanating from the mutant lesions propagated bidirectionally throughout the Tsr signaling domain and did not dissipate appreciably with distance, implying conformational coupling between subdomains. These behaviors proved intrinsic to Tsr homodimers and independent of higher order signaling complexes. AlphaFold 3 atomic models of the mutant receptors exhibited structural changes that would likely affect local helix packing interactions at the mutant sites. One member of each ON-OFF mutant pair appeared to reduce packing stability, whereas the other enhanced packing stability. This analysis pinpointed two sites of structural logic inversion (“entropic switches”) in the Tsr transmission path. Kinase-OFF lesions appeared to be stabilizing at the input and output segments of the cytoplasmic domain but destabilizing in the intervening signaling region that contains the modification sites for sensory adaptation. These findings support the notion of chemoreceptor signaling through opposed dynamic switches and provide new insights into the mechanism of kinase output control. This work also highlights the powerful interplay possible between cellular signaling readouts and AF3-generated models of mutant proteins.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"438 5","pages":"Article 169614"},"PeriodicalIF":4.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145832080","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

Targeting DNA Topoisomerase I for the Treatment of Cancer: Past, Present and Future 靶向DNA拓扑异构酶I治疗癌症：过去，现在和未来。

IF 4.5 2区生物学

Journal of Molecular Biology Pub Date : 2026-03-01 Epub Date: 2025-08-21 DOI: 10.1016/j.jmb.2025.169401

Annapoorna Venkatachalam, Scott H. Kaufmann

引用次数: 0