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Distinct binding modes drive the broad neutralization profile of two persistent influenza hemagglutinin stem-specific antibody lineages

IF 5.7 2区生物学

Structure Pub Date : 2025-03-19 DOI: 10.1016/j.str.2025.02.010

Grace E. Mantus, Gabriele Cerutti, Michael Chambers, Rebecca A. Gillespie, Geoffrey D. Shimberg, Abby Spangler, Jason Gorman, Tongqing Zhou, Chen-Hsiang Shen, Masaru Kanekiyo, Peter D. Kwong, Lawrence Shapiro, Sarah F. Andrews

{"title":"Distinct binding modes drive the broad neutralization profile of two persistent influenza hemagglutinin stem-specific antibody lineages","authors":"Grace E. Mantus, Gabriele Cerutti, Michael Chambers, Rebecca A. Gillespie, Geoffrey D. Shimberg, Abby Spangler, Jason Gorman, Tongqing Zhou, Chen-Hsiang Shen, Masaru Kanekiyo, Peter D. Kwong, Lawrence Shapiro, Sarah F. Andrews","doi":"10.1016/j.str.2025.02.010","DOIUrl":"https://doi.org/10.1016/j.str.2025.02.010","url":null,"abstract":"Elicitation of antibodies to the influenza hemagglutinin stem is a critical part of universal influenza vaccine strategies. While numerous broadly reactive stem antibodies have been isolated, our understanding of how these antibodies mature within the human B cell repertoire is limited. Here, we isolated and tracked two stem-specific antibody lineages over a decade in a single participant that received multiple seasonal and pandemic influenza vaccinations. Despite similar binding and neutralization profiles, antibodies from these lineages utilized fundamentally different interactions to engage the central epitope on the influenza stem. Structural analysis of an unmutated common ancestor from one lineage identified critical residues that were the main drivers of increased affinity and breadth to group 1 influenza subtypes. These observations demonstrate the heterogeneous pathways by which stem-specific antibodies can mature within the human B cell repertoire.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"197 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653797","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

Molecular basis of Ad5-nCoV vaccine-induced immunogenicity

IF 5.7 2区生物学

Structure Pub Date : 2025-03-19 DOI: 10.1016/j.str.2025.02.009

Dongyang Dong, Yutong Song, Shipo Wu, Busen Wang, Cheng Peng, Weiping Zhang, Weizheng Kong, Zheyuan Zhang, Jingwen Song, Li-Hua Hou, Sai Li

{"title":"Molecular basis of Ad5-nCoV vaccine-induced immunogenicity","authors":"Dongyang Dong, Yutong Song, Shipo Wu, Busen Wang, Cheng Peng, Weiping Zhang, Weizheng Kong, Zheyuan Zhang, Jingwen Song, Li-Hua Hou, Sai Li","doi":"10.1016/j.str.2025.02.009","DOIUrl":"https://doi.org/10.1016/j.str.2025.02.009","url":null,"abstract":"Ad5-nCoV (Convidecia) is listed for emergency use against COVID-19 by the World Health Organization (WHO) and has been globally administered to millions of people. It utilizes human adenovirus 5 (Ad5) replication-incompetent vector to deliver the spike (S) protein gene from various SARS-CoV-2 strains. Despite promising clinical data, the molecular mechanism underlying its high immunogenicity and adverse reactions remain incompletely understood. Here, we primarily applied cryo-electron tomography (cryo-ET), fluorescence microscopy and mass spectrometry to analyze the Ad5-nCoV_Wu and Ad5-nCoV_O vaccine-induced S antigens. These antigens encode the unmodified SARS-CoV-2 Wuhan-Hu-1 S gene and the stabilized Omicron S gene, respectively. Our findings highlight the structural integrity, antigenicity, and dense distribution on cell membrane of the vaccine-induced S proteins. Ad5-nCoV_O induced S proteins exhibit improved stability and reduced syncytia formation among inoculated cells. Our work demonstrates that Ad5-nCoV is a prominent platform for antigen induction and cryo-ET can be a useful technique for vaccine characterization and development.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"6 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653796","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

Next-generation small molecule inhibitors of clathrin function acutely inhibit endocytosis

IF 5.7 2区生物学

Structure Pub Date : 2025-03-19 DOI: 10.1016/j.str.2025.02.011

André Horatscheck, Michael Krauß, Haydar Bulut, Valerie Chambon, Massilullah Shafaq Zadah, Estelle Dransart, Kimberly Peloza, Karine F. Santos, Mark J. Robertson, Kate Prichard, Sandra Miksche, Silke Radetzki, Jens-Peter von Kries, Markus C. Wahl, Adam McCluskey, Ludger Johannes, Volker Haucke, Marc Nazaré

{"title":"Next-generation small molecule inhibitors of clathrin function acutely inhibit endocytosis","authors":"André Horatscheck, Michael Krauß, Haydar Bulut, Valerie Chambon, Massilullah Shafaq Zadah, Estelle Dransart, Kimberly Peloza, Karine F. Santos, Mark J. Robertson, Kate Prichard, Sandra Miksche, Silke Radetzki, Jens-Peter von Kries, Markus C. Wahl, Adam McCluskey, Ludger Johannes, Volker Haucke, Marc Nazaré","doi":"10.1016/j.str.2025.02.011","DOIUrl":"https://doi.org/10.1016/j.str.2025.02.011","url":null,"abstract":"Clathrin-mediated endocytosis (CME) is the predominant endocytic pathway in eukaryotic cells and a major regulator of cell physiology as it facilitates the internalization of receptors, channels, and transporters and viral entry. The clathrin terminal domain acts as a central protein interaction hub within the endocytic protein network. Previously described inhibitors of CME display off-target activities that result in cytotoxicity, providing limitations to their use. We report the development and characterization of next-generation small molecule inhibitors of clathrin terminal domain function. These compounds termed Pitstop 2c and Pitstop 2d occupy the binding site within the clathrin terminal domain for endocytic protein ligands including epsin, resulting in potent inhibition of receptor-mediated endocytosis and reduced entry of vesicular stomatitis virus (VSV) with minimal cytotoxic side effects. Next-generation Pitstops thus provide an improved toolset to address clathrin function in cell physiology with potential applications as inhibitors of virus and pathogen entry.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"32 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653800","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 and dynamics of a nucleosome core particle based on Widom 603 DNA sequence

IF 5.7 2区生物学

Structure Pub Date : 2025-03-17 DOI: 10.1016/j.str.2025.02.007

Grigoriy A. Armeev, Andrey V. Moiseenko, Nikita A. Motorin, Dmitriy A. Afonin, Lei Zhao, Veniamin A. Vasilev, Pavel D. Oleinikov, Grigory S. Glukhov, Georgy S. Peters, Vasily M. Studitsky, Alexey V. Feofanov, Alexey K. Shaytan, Xiangyan Shi, Olga S. Sokolova

{"title":"Structure and dynamics of a nucleosome core particle based on Widom 603 DNA sequence","authors":"Grigoriy A. Armeev, Andrey V. Moiseenko, Nikita A. Motorin, Dmitriy A. Afonin, Lei Zhao, Veniamin A. Vasilev, Pavel D. Oleinikov, Grigory S. Glukhov, Georgy S. Peters, Vasily M. Studitsky, Alexey V. Feofanov, Alexey K. Shaytan, Xiangyan Shi, Olga S. Sokolova","doi":"10.1016/j.str.2025.02.007","DOIUrl":"https://doi.org/10.1016/j.str.2025.02.007","url":null,"abstract":"Nucleosomes are fundamental elements of chromatin organization that participate in compacting genomic DNA and serve as targets for the binding of numerous regulatory proteins. Currently, over 500 different nucleosome structures are known. Despite the large number of nucleosome structures, all of them were formed on only about twenty different DNA sequences. Using cryo-electron microscopy, we determined the structure of the nucleosome formed on a high-affinity Widom 603 DNA sequence at 4 Å resolution; an atomic model was built. We proposed an integrative modeling approach to study the nucleosomal DNA unwrapping based on the cryoelectron microscopy (cryo-EM) data. We also demonstrated the DNA unwrapping of the Widom 603 nucleosome using small angle X-ray scattering and single particle Förster resonance energy transfer measurements. Our results are consistent with the asymmetry of nucleosomal DNA unwrapping. Our data revealed the dependence of nucleosome structure and dynamics on the sequence of nucleosomal DNA.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"6 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635600","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

Structures and mechanisms of the ABC transporter ABCB1 from Arabidopsis thaliana

IF 5.7 2区生物学

Structure Pub Date : 2025-03-17 DOI: 10.1016/j.str.2025.02.008

Qian Chen, Li Zhu, Sufen Zhang, Shuai Qiao, Zhong Jie Ding, Shao Jian Zheng, Jiangtao Guo, Nannan Su

引用次数: 0

The structure and function of the DNA binding domain of class B MpARF2 share more traits with class A AtARF5 than to that of class B AtARF1

IF 5.7 2区生物学

Structure Pub Date : 2025-03-13 DOI: 10.1016/j.str.2025.02.006

Isidro Crespo, Marc Malfois, Juriaan Rienstra, Aleix Tarrés-Solé, Willy van den Berg, Dolf Weijers, Dirk Roeland Boer

{"title":"The structure and function of the DNA binding domain of class B MpARF2 share more traits with class A AtARF5 than to that of class B AtARF1","authors":"Isidro Crespo, Marc Malfois, Juriaan Rienstra, Aleix Tarrés-Solé, Willy van den Berg, Dolf Weijers, Dirk Roeland Boer","doi":"10.1016/j.str.2025.02.006","DOIUrl":"https://doi.org/10.1016/j.str.2025.02.006","url":null,"abstract":"Plant development is primarily controlled by the auxin phytohormones, which activate the auxin response factors (ARFs). Although the nuclear auxin pathway (NAP) is well studied, little is known on how ARFs specifically select target genes. Here, we investigated the DNA binding mechanism of ARF DNA binding domains (DBDs) from the activator class A and repressor class B in two evolutionary distant plant species, Marchantia polymorpha and Arabidopsis thaliana using fluorescence anisotropy, size exclusion chromatography, macromolecular crystallography (MX), and small-angle X-ray scattering (SAXS). We find that the previously proposed molecular caliper model, which partially explains the variability in binding of the ARFs to DNA, has been preserved throughout evolution. Our results show that the DBD of class B MpARF2 behaves more like class A AtARF5 than class B AtARF1. These findings suggest that DNA recognition of ARFs has diverged independently of the transcriptional output, which has significant implications for understanding diverse responses to auxin.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"15 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608703","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 a putative terminal amidation domain in natural product biosynthesis

IF 5.7 2区生物学

Structure Pub Date : 2025-03-13 DOI: 10.1016/j.str.2025.02.005

Michael R. Rankin, Dheeraj Khare, Lena Gerwick, David H. Sherman, William H. Gerwick, Janet L. Smith

引用次数: 0

Automated model-free analysis of cryo-EM volume ensembles with SIREn

IF 5.7 2区生物学

Structure Pub Date : 2025-03-10 DOI: 10.1016/j.str.2025.02.004

Laurel F. Kinman, Maria V. Carreira, Barrett M. Powell, Joseph H. Davis

引用次数: 0

The ABC transporter MsbA in a dozen environments

IF 5.7 2区生物学

Structure Pub Date : 2025-03-07 DOI: 10.1016/j.str.2025.02.002

Lea Hoffmann, Anika Baier, Lara Jorde, Michael Kamel, Jan-Hannes Schäfer, Kilian Schnelle, Alischa Scholz, Dmitry Shvarev, Jaslyn E.M. M. Wong, Kristian Parey, Dovile Januliene, Arne Moeller

{"title":"The ABC transporter MsbA in a dozen environments","authors":"Lea Hoffmann, Anika Baier, Lara Jorde, Michael Kamel, Jan-Hannes Schäfer, Kilian Schnelle, Alischa Scholz, Dmitry Shvarev, Jaslyn E.M. M. Wong, Kristian Parey, Dovile Januliene, Arne Moeller","doi":"10.1016/j.str.2025.02.002","DOIUrl":"https://doi.org/10.1016/j.str.2025.02.002","url":null,"abstract":"High-resolution structure determination of membrane proteins typically requires reconstitution into artificial membrane mimics. The choice of the specific membrane substitute can strongly affect the protein’s specific activity, stability, and conformational spectrum, potentially leading to errors or misinterpretation during analysis. The bacterial ATP-binding cassette transporter MsbA is a prominent example of such environment-specific bias. Here, we present a systematic analysis of the conformational spectrum of MsbA, stabilized in a dozen environments, using cryoelectron microscopy (cryo-EM), and show pronounced feedback between the membrane mimetics and the transporter. Detergents generally favor wide inward-facing conformations while nanodiscs induce narrower conformations. Notably, only in three tested environments, MsbA samples the full movement of the nucleotide-binding domains, including narrow and wide conformations. We expect this study to serve as a blueprint for other membrane proteins, even where a structural reaction to the hydrophobic environment is not directly visible but still critical for the proteins’ function.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"16 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569573","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

HuR prevents amyloid beta-induced phase separation of miRNA-bound Ago2 to RNA-processing bodies

IF 5.7 2区生物学

Structure Pub Date : 2025-03-07 DOI: 10.1016/j.str.2025.02.003

Sritama Ray, Sumangal Roychowdhury, Yogaditya Chakrabarty, Saikat Banerjee, Alisiara Hobbs, Krishnananda Chattopadhyay, Kamalika Mukherjee, Suvendra N. Bhattacharyya

{"title":"HuR prevents amyloid beta-induced phase separation of miRNA-bound Ago2 to RNA-processing bodies","authors":"Sritama Ray, Sumangal Roychowdhury, Yogaditya Chakrabarty, Saikat Banerjee, Alisiara Hobbs, Krishnananda Chattopadhyay, Kamalika Mukherjee, Suvendra N. Bhattacharyya","doi":"10.1016/j.str.2025.02.003","DOIUrl":"https://doi.org/10.1016/j.str.2025.02.003","url":null,"abstract":"Phase separation into membrane-less organelles regulates protein activity in eukaryotic cells. miRNA-repressed mRNAs and Ago proteins localize to RNA-processing bodies (P-bodies), which are subcellular structures formed by several RNA-binding and regulatory proteins. Ago2, the essential miRNA-binding protein, forms a complex with miRNAs to repress protein synthesis by binding to mRNAs and targeting them to P-bodies. However, factors controlling Ago2 and miRNA-repressed mRNA compartmentalization into P-bodies are not fully understood. We developed a detergent-permeabilized cell-based assay system to observe the phase separation of exogenously added Ago2 into P-bodies in vitro. We observed that miRNA binding to Ago2 is essential for its localization to P-bodies, which is also ATP dependent. Osmolarity and salt concentration also affect Ago2 compartmentalization to P-bodies. Amyloid beta oligomers enhance Ago2 targeting to P-bodies by slowing down cellular Ago2 dynamics and inhibiting mTORC1 activity. However, the RNA-binder HuR disrupts P-body targeting by “sponging” out Ago2-associated miRNAs.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"85 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569639","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