Journal of Molecular Biology最新文献_第10页

Allosteric Anti-KLK4 Antibody Development for Targeted Anti-cancer Effects in Ovarian Carcinoma. 抗klk4变构抗体在卵巢癌中的靶向抗癌作用

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-03-26 DOI: 10.1016/j.jmb.2025.169101

Nikolaos A Afratis, Blake T Riley, Peter G Chandler, Ashley M Buckle, Irit Sagi

{"title":"Allosteric Anti-KLK4 Antibody Development for Targeted Anti-cancer Effects in Ovarian Carcinoma.","authors":"Nikolaos A Afratis, Blake T Riley, Peter G Chandler, Ashley M Buckle, Irit Sagi","doi":"10.1016/j.jmb.2025.169101","DOIUrl":"10.1016/j.jmb.2025.169101","url":null,"abstract":"<p><p>Kallikrein-related peptidases (KLKs) have garnered significant interest in the field of biomedical research due to their diverse roles in various physiological and pathological processes. However, the structurally conserved active site of the KLK family presents challenges for the development of specific inhibitors. Given the pro-tumorigenic roles KLKs play in various cancers, identifying new avenues for specific inhibition is therefore vital. Here, we introduce a novel approach to target a distinct KLK4 sequence by a unique immunization approach for monoclonal antibody generation, targeting loop 3, a region of high sequence and structural diversity as a candidate for allosteric control of KLK4 activity. Immunisation produced an antibody capable of interacting with both KLK4 and loop 3 with high affinity, which inhibited KLK4 proteolytic activity, and hindered proliferation and migration in ovarian cancer cell lines. Encouragingly, its potential application extends to preclinical models characterized by KLK4 overexpression. Our findings underscore the promise of this novel approach to addressing the challenges of specifically inhibiting ubiquitous serine proteases, with particular relevance to targeting KLK4, a protease instrumental in the progression of ovarian carcinoma and other cancer types.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169101"},"PeriodicalIF":4.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741833","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 Life and Times of Brain Autophagic Vesicles. 脑自噬囊泡的寿命和次数。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-03-26 DOI: 10.1016/j.jmb.2025.169105

Lisa Gambarotto, Erin Wosnitzka, Vassiliki Nikoletopoulou

引用次数: 0

K_DSAXS: A Tool for Analyzing Binding Equilibria With SAXS Data Using Explicit Models. KDSAXS：一个用显式模型分析SAXS数据的绑定均衡的工具。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-03-25 DOI: 10.1016/j.jmb.2025.169103

Tiago Gomes, Lidia Ruiz, Pau Martin-Malpartida, Pau Bernadó, António M Baptista, Maria J Macias, Tiago N Cordeiro

{"title":"K<sub>D</sub>SAXS: A Tool for Analyzing Binding Equilibria With SAXS Data Using Explicit Models.","authors":"Tiago Gomes, Lidia Ruiz, Pau Martin-Malpartida, Pau Bernadó, António M Baptista, Maria J Macias, Tiago N Cordeiro","doi":"10.1016/j.jmb.2025.169103","DOIUrl":"https://doi.org/10.1016/j.jmb.2025.169103","url":null,"abstract":"<p><p>K<sub>D</sub>SAXS is a computational tool for estimating dissociation constants (K<sub>D</sub>) from small-angle X-ray scattering (SAXS) titration experiments. By combining ensemble analysis with mass-balance equations, K<sub>D</sub>SAXS effectively models complex equilibria involving multiple species, ranging from simple oligomerization to transient and multivalent interactions, including intrinsically disordered proteins. For each species in equilibrium, the tool supports the integration of theoretical scattering profiles derived from ensemble structural models, X-ray crystallography, NMR, AlphaFold predictions, or molecular dynamics simulations. With its intuitive dashboard interface, K<sub>D</sub>SAXS enables researchers to input SAXS titration data, validate structural models and interactions, and compute species-specific scattering profiles. Additionally, it determines the relative populations of biomolecular species in equilibrium across user-defined Kᴅ ranges and concentrations. Applications of K<sub>D</sub>SAXS to systems such as beta-lactoglobulin oligomerization and the PCNA-p15PAF complex highlight its capacity to resolve complex equilibria and deliver accurate K<sub>D</sub> estimations. As an open-source platform, K<sub>D</sub>SAXS bridges computational and experimental methodologies, advancing SAXS-based analysis of macromolecular interactions and enhancing insights into dynamic biological systems. K<sub>D</sub>SAXS is freely accessible as a web server at https://kdsaxs.itqb.unl.pt.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169103"},"PeriodicalIF":4.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957918","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 Secret Life of N¹-methyladenosine: A Review on its Regulatory Functions. n1 -甲基腺苷的秘密生命：其调控功能综述。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-03-24 DOI: 10.1016/j.jmb.2025.169099

Nhi Yen Tran Nguyen, Xisheng Liu, Anindya Dutta, Zhangli Su

引用次数: 0

Kinetic Investigation of Resistance to Islatravir Conferred by Mutations in HIV-1 Reverse Transcriptase HIV-1逆转录酶突变对Islatravir耐药的动力学研究。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-03-24 DOI: 10.1016/j.jmb.2025.169100

Nikita Zalenski, Brianna R. Meredith, Derek J. Savoie, Mohamed J. Naas, David J. Suo, Daniel Betancourt, Turner W. Seay, Zucai Suo

{"title":"Kinetic Investigation of Resistance to Islatravir Conferred by Mutations in HIV-1 Reverse Transcriptase","authors":"Nikita Zalenski, Brianna R. Meredith, Derek J. Savoie, Mohamed J. Naas, David J. Suo, Daniel Betancourt, Turner W. Seay, Zucai Suo","doi":"10.1016/j.jmb.2025.169100","DOIUrl":"10.1016/j.jmb.2025.169100","url":null,"abstract":"<div><div>Islatravir (EFdA) is a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) that potently blocks HIV-1 replication <em>in vivo</em>. Its unique structural features in contrast to nucleoside reverse transcriptase inhibitors (NRTIs), particularly the 4′-ethynyl and 3′-hydroxy groups, contribute to its high clinical potency. Once intracellularly activated to EFdA 5′-triphosphate (EFdA-TP), it competes with dATP for incorporation by HIV-1 reverse transcriptase (RT) during HIV-1 genomic replication. The 4′-ethynyl group of incorporated EFdA-MP interacts with a hydrophobic pocket of HIV-1 RT, hindering DNA translocation and terminating DNA synthesis. The M184V mutation, commonly associated with resistance to NRTIs such as lamivudine and emtricitabine, and the M184V/A114S mutations, both located within the hydrophobic pocket, were shown to reduce Islatravir susceptibility in cell-based viral resistance selection assays. To elucidate the mechanisms by which these mutations affect Islatravir inhibition, we employed pre-steady-state kinetics to investigate their impact on EFdA-TP incorporation by HIV-1 RT using both DNA and RNA templates. We found that M184V had a modest effect on EFdA-TP incorporation efficiency, increasing it 2-fold with the DNA template and decreasing it 3-fold with the RNA template. In contrast, M184V/A114S significantly inhibited EFdA-TP incorporation, reducing its incorporation efficiency 5.4-fold with the DNA template and 181-fold with the RNA template. These reductions were primarily attributable to corresponding decreases in EFdA-TP incorporation rate constants of 18-fold and 105-fold, respectively. These results suggest that, unlike FDA-approved NRTIs, the clinical efficacy of Islatravir, may not be substantially compromised by the M184V mutation alone but will be significantly reduced by the M184V/A114S mutations.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 12","pages":"Article 169100"},"PeriodicalIF":4.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727495","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

NNSFMDA: Lightweight Transformer Model with Bounded Nuclear Norm Minimization for Microbe-Drug Association Prediction NNSFMDA：基于有界核范数最小化和简化变压器的微生物-药物关联预测新模型。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-03-24 DOI: 10.1016/j.jmb.2025.169086

Shuyuan Yang , Xin Liu , Yiming Chen , Xiangyi Wang , Zhen Zhang , Lei Wang

{"title":"NNSFMDA: Lightweight Transformer Model with Bounded Nuclear Norm Minimization for Microbe-Drug Association Prediction","authors":"Shuyuan Yang , Xin Liu , Yiming Chen , Xiangyi Wang , Zhen Zhang , Lei Wang","doi":"10.1016/j.jmb.2025.169086","DOIUrl":"10.1016/j.jmb.2025.169086","url":null,"abstract":"<div><div>Identifying potential connections between microbe-drug pairs play an important role in drug discovery and clinical treatment. Techniques like graph neural networks effectively derive accurate node representations from sparse topologies,however, they struggle with over-smoothing and over-compression, and their interpretability is relatively poor. Conversely, mathematical methods with low-rank approximations are interpretable but often get trapped in local optima. To address these issues, we propose a new prediction model named NNSFMDA, in which, the bounded nuclear norm minimization and the simplified transformer were combined to infer possible drug-microbe associations. In NNSFMDA, we first constructed a heterogeneous microbe-drug network by integrating multiple microbe and drug similarity metrics, according to which, we subsequently transformed the prediction problem to a matrix filling problem, and then, iteratively approximated the matrix by minimizing the number of bounded nuclear norm. Finally, based on the newly-filled matrix, we introduced a simplified transformer to estimate possible scores of microbe-drug pairs. Results showed that NNSFMDA could achieve reliable AUC value of 0.98, which outperformed existing state-of-the-art competitive methods. In the experimental section, ablation experiments and modular analyses further demonstrate the superiority of the model, and case studies of microbe-drug associations confirm the validity of the model. These tests have all highlighted the potential of the NNSFMDA to predict latent microbe-drug associations in the future.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 12","pages":"Article 169086"},"PeriodicalIF":4.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727496","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

Pioneers in Molecular Biology 分子生物学的先驱。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-03-20 DOI: 10.1016/j.jmb.2025.169098

Michael F. Summers (Editor in Chief)

引用次数: 0

The 2.3 Å Structure of A21, a Protein Component of the Conserved Poxvirus Entry-Fusion Complex 保守痘病毒入口融合复合体蛋白组分A21的2.3 Å结构

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-03-19 DOI: 10.1016/j.jmb.2025.169097

Ulrike S. Diesterbeck , Liya A. Muslinkina , Apostolos G. Gittis , Kavita Singh , Bernard Moss , David N. Garboczi

{"title":"The 2.3 Å Structure of A21, a Protein Component of the Conserved Poxvirus Entry-Fusion Complex","authors":"Ulrike S. Diesterbeck , Liya A. Muslinkina , Apostolos G. Gittis , Kavita Singh , Bernard Moss , David N. Garboczi","doi":"10.1016/j.jmb.2025.169097","DOIUrl":"10.1016/j.jmb.2025.169097","url":null,"abstract":"<div><div>Poxviruses are exceptional in having an entry-fusion complex (EFC) consisting of eleven conserved proteins embedded in the membrane of mature virions. With the goal of understanding the function of the EFC, extensive efforts have been made to determine the structures and roles of its components, and to date, structures have been determined for nine of the eleven proteins. Here, we report the crystal structure of A21, the 10th EFC protein, comprising two α-helices clasping a twisted antiparallel β-sheet stabilized by two conserved disulfide bonds. The stability of each of the three A21 loops is provided by hydrogen bonds between main-chain atoms and several highly conserved residues, making the overall fold of A21 and its orthologs resilient to evolutionary change. Based on AlphaFold modeling and phylogenetic analysis of A21, we suggest that its highly conserved N-terminal transmembrane domain and C-terminal α-helix enable A21 integration into EFC, where it primarily interacts with the G3/L5 subcomplex and the smallest of EFC components, the O3 protein.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 12","pages":"Article 169097"},"PeriodicalIF":4.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673130","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

Connecting tRNA Charging and Decoding through the Axis of Nucleotide Modifications at Position 37. 通过37位核苷酸修饰轴连接tRNA充电和解码。

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-03-18 DOI: 10.1016/j.jmb.2025.169095

Isao Masuda, Henri McGuigan, Sunita Maharjan, Yuka Yamaki, Ya-Ming Hou

{"title":"Connecting tRNA Charging and Decoding through the Axis of Nucleotide Modifications at Position 37.","authors":"Isao Masuda, Henri McGuigan, Sunita Maharjan, Yuka Yamaki, Ya-Ming Hou","doi":"10.1016/j.jmb.2025.169095","DOIUrl":"10.1016/j.jmb.2025.169095","url":null,"abstract":"<p><p>Charging and decoding of tRNA are two steps in an elongation cycle of protein synthesis that embody the essence of the genetic code. In this embodiment, the amino acid charged to the 3'-end of a tRNA is delivered to the corresponding codon via the base pairing interaction between the anticodon of the tRNA and the codon in the ribosome decoding site. Previous work has shown that the nucleotide base at position 37 on the 3'-side of the anticodon can connect charging with decoding in one elongation cycle, providing an axis to coordinate these two steps in the making of a new peptide bond. However, as much of the previous work used tRNA transcripts as substrates, lacking any post-transcriptional modification, the role of the post-transcriptional modification at position 37 in this axis has remained unknown. Here we summarize recent work that has uncovered the modifications at position 37 that are important for both charging and decoding. We find that m<sup>1</sup>G37 and t<sup>6</sup>A37 are two such modifications. This review serves as a template for further discovery of tRNA modifications at position 37 that connect charging with decoding to provide the basis for better understanding of tRNA biology in human health and disease.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":" ","pages":"169095"},"PeriodicalIF":4.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668700","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

Distinct Roles of SARS-CoV-2 N Protein and NFP in Host Cell Response Modulation sars - cov - 2n蛋白和NFP在宿主细胞应答调节中的独特作用

IF 4.7 2区生物学

Journal of Molecular Biology Pub Date : 2025-03-17 DOI: 10.1016/j.jmb.2025.169094

Hsin-Chi Lan , Bo-Yi Hou , Shu-Ting Chang , Cheng-Yu Kuo , Wei-Chen Wang , Ya-Li Yao , Hung-Yi Wu , Chien-Chen Lai , Wen-Ming Yang

{"title":"Distinct Roles of SARS-CoV-2 N Protein and NFP in Host Cell Response Modulation","authors":"Hsin-Chi Lan , Bo-Yi Hou , Shu-Ting Chang , Cheng-Yu Kuo , Wei-Chen Wang , Ya-Li Yao , Hung-Yi Wu , Chien-Chen Lai , Wen-Ming Yang","doi":"10.1016/j.jmb.2025.169094","DOIUrl":"10.1016/j.jmb.2025.169094","url":null,"abstract":"<div><div>The SARS-CoV-2 nucleocapsid (N) protein is crucial for viral replication and modulation of host cell responses. Here, we identify and characterize a novel N-fusion protein, designated NFP. NFP is derived from an alternative open reading frame spanning the N gene and the non-structural protein 1 (NSP1) sequence. While NFP shares some functional domains with the canonical N protein, it exhibits distinct structural features and protein interactions. NFP retains the ability to dimerize and bind RNA but lacks the formation of biomolecular condensates associated with N. Notably, NFP can dominantly interfere with N’s condensate formation capacity when co-expressed. Functionally, NFP partially suppresses stress granule (SG) formation through a G3BP1-independent mechanism but gains the ability to interact with G3BP1 in the presence of N, potentially through N-NFP heterodimer formation. Post-translational modifications, particularly ubiquitination of specific lysine residues (K374 in N and K502 in NFP), differentially regulate the subcellular localization, SG inhibition, and cell cycle regulation activities of N and NFP. Our findings establish NFP as a distinct viral effector protein that modulates host cellular environments through both conserved and unique mechanisms compared to the canonical N protein, providing insights into SARS-CoV-2 pathogenesis and potential therapeutic targets.</div></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":"437 12","pages":"Article 169094"},"PeriodicalIF":4.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661759","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