Structure最新文献_第9页

Acquisition of quaternary trimer interaction as a key step in the lineage maturation of a broad and potent HIV-1 neutralizing antibody 获得四聚三聚体相互作用是广泛和有效的HIV-1中和抗体谱系成熟的关键步骤

IF 5.7 2区生物学

Structure Pub Date : 2025-05-23 DOI: 10.1016/j.str.2025.04.020

Qingbo Liu, Ruth J. Parsons, Kevin Wiehe, Robert J. Edwards, Kevin O. Saunders, Peng Zhang, Huiyi Miao, Kedamawit Tilahun, Julia Jones, Yue Chen, Bhavna Hora, Wilton B. Williams, David Easterhoff, Xiao Huang, Katarzyna Janowska, Katayoun Mansouri, Barton F. Haynes, Priyamvada Acharya, Paolo Lusso

{"title":"Acquisition of quaternary trimer interaction as a key step in the lineage maturation of a broad and potent HIV-1 neutralizing antibody","authors":"Qingbo Liu, Ruth J. Parsons, Kevin Wiehe, Robert J. Edwards, Kevin O. Saunders, Peng Zhang, Huiyi Miao, Kedamawit Tilahun, Julia Jones, Yue Chen, Bhavna Hora, Wilton B. Williams, David Easterhoff, Xiao Huang, Katarzyna Janowska, Katayoun Mansouri, Barton F. Haynes, Priyamvada Acharya, Paolo Lusso","doi":"10.1016/j.str.2025.04.020","DOIUrl":"https://doi.org/10.1016/j.str.2025.04.020","url":null,"abstract":"Although most broadly neutralizing antibodies (bNAbs) specific for the CD4-binding site (CD4-BS) of HIV-1 interact with a single gp120 protomer, a few mimic the quaternary binding mode of CD4, making contact with a second protomer through elongated heavy chain framework 3 (FRH3) or complementarity-determining region 1 (CDRH1) loops. Here, we show that a CDRH3-dominated anti-CD4-BS bNAb, CH103, establishes quaternary interaction despite regular-length FRH3 and CDRH1. This quaternary interaction is critical for neutralization and is primarily mediated by two FRH3 acidic residues that were sequentially acquired and subjected to strong positive selection during CH103 maturation. Cryoelectron microscopy (cryo-EM) structures confirmed the role of the two FRH3 acidic residues in mediating quaternary contact and demonstrated that CH103 reaches the adjacent gp120 protomer by virtue of its unique angle of approach. Thus, the acquisition of quaternary interaction may constitute a key step in the lineage maturation of a broad and potent HIV-1 neutralizing antibody.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"24 8 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122795","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

Unprocessed BMP9 precursor is an intrinsic antagonist for its active growth factor 未加工的BMP9前体是其活性生长因子的内在拮抗剂

IF 5.7 2区生物学

Structure Pub Date : 2025-05-23 DOI: 10.1016/j.str.2025.04.021

Weida Zhang, Yuanyuan Zhang, Weidong Mao, Tao Huang, Xinrong Yu, Xiaohong Qin, Li-Zhi Mi

引用次数: 0

Chloride binding does not influence prestin motor speed at very high frequencies in the mouse outer hair cell 在小鼠外毛细胞中，氯离子结合在非常高的频率下不影响prestin运动速度

IF 5.7 2区生物学

Structure Pub Date : 2025-05-21 DOI: 10.1016/j.str.2025.04.019

Jun-Ping Bai, Chenou Zhang, Iman Bahader, Nicola Strenzke, Vijay Renigunta, Dominik Oliver, Dhasakumar Navaratnam, Oliver Beckstein, Joseph Santos-Sacchi

{"title":"Chloride binding does not influence prestin motor speed at very high frequencies in the mouse outer hair cell","authors":"Jun-Ping Bai, Chenou Zhang, Iman Bahader, Nicola Strenzke, Vijay Renigunta, Dominik Oliver, Dhasakumar Navaratnam, Oliver Beckstein, Joseph Santos-Sacchi","doi":"10.1016/j.str.2025.04.019","DOIUrl":"https://doi.org/10.1016/j.str.2025.04.019","url":null,"abstract":"Prestin (SLC26A5) promotes mechanical feedback via outer hair cells (OHC) within the organ of Corti, governed by voltage-dependent kinetics of its charge movements; namely, nonlinear-capacitance (NLC). We study NLC frequency response in mouse OHC membrane patches. The characteristic frequency cut-off (Fis) is 27 kHz. Single point mutations within prestin’s chloride binding pocket (S396E and S398E) lack usual anion influence. In agreement, we show absence of anion binding in these mutants through molecular dynamics (MD) simulations. NLC Fis in S396E knock-in mice is unaltered, indicating that high frequency activity is not governed by chloride but likely by viscoelastic loads. Also, the allosteric action of chloride does not underlie piezoelectric-like behavior in prestin, since tension sensitivity of S396E NLC is comparable to WT. Because structures of all studied species appear indistinguishable, with analogous chloride binding pockets, prestin performance likely evolved by modifying, not its protein-anion interaction, but instead mechanical loads on the protein.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"94 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103984","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 molecular mechanisms of visual chromophore release from cellular retinaldehyde-binding protein 细胞视黄醛结合蛋白视觉发色团释放的分子机制

IF 5.7 2区生物学

Structure Pub Date : 2025-05-21 DOI: 10.1016/j.str.2025.04.018

Daniel Santos, Lorenzo Foglia, Philip D. Kiser, Alvin Yu

{"title":"The molecular mechanisms of visual chromophore release from cellular retinaldehyde-binding protein","authors":"Daniel Santos, Lorenzo Foglia, Philip D. Kiser, Alvin Yu","doi":"10.1016/j.str.2025.04.018","DOIUrl":"https://doi.org/10.1016/j.str.2025.04.018","url":null,"abstract":"Cellular retinaldehyde-binding protein (CRALBP) is an 11-cis-retinoid binding protein operating within the visual cycle. CRALBP serves as the terminal acceptor of 11-cis-retinaldehyde (11cRAL) produced within the retinal pigment epithelium (RPE) and mediates 11cRAL transport to the RPE apical microvilli. Crystallographic structures of CRALBP revealed that the 11cRAL-binding pocket is sealed off from bulk solvent, indicating a necessity for conformational changes to allow ligand egress. Here, we performed long timescale all-atom molecular dynamics simulations of CRALBP to elucidate the mechanisms of ligand release. CRALBP exhibits slower diffusive behavior in the presence of membranes containing negatively charged phospholipids, which bind to an exposed cationic pocket in CRALBP. Umbrella sampling calculations revealed thermodynamically likely pathways for 11cRAL egress. Our data suggest that the CRALBP-acidic phospholipid interaction facilitates 11cRAL release through allosteric, conformational changes that perturb the binding site, lowering ligand affinity. These findings offer insights into the molecular pathology of CRALBP-associated retinopathy.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"9 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103989","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

Structural study on human microbiome-derived polyketide synthases that assemble genotoxic colibactin 组装基因毒性大肠杆菌素的人类微生物源性聚酮合成酶的结构研究

IF 5.7 2区生物学

Structure Pub Date : 2025-05-16 DOI: 10.1016/j.str.2025.04.017

Minjae Kim, Jinwoo Kim, Gyu Sung Lee, Paul Dominic B. Olinares, Yougant Airan, Jasmine L. Chow, Jongseok Park, Yujin Jeong, Jiho Park, Brian T. Chait, Seth B. Herzon, Chung Sub Kim, Jin Young Kang

{"title":"Structural study on human microbiome-derived polyketide synthases that assemble genotoxic colibactin","authors":"Minjae Kim, Jinwoo Kim, Gyu Sung Lee, Paul Dominic B. Olinares, Yougant Airan, Jasmine L. Chow, Jongseok Park, Yujin Jeong, Jiho Park, Brian T. Chait, Seth B. Herzon, Chung Sub Kim, Jin Young Kang","doi":"10.1016/j.str.2025.04.017","DOIUrl":"https://doi.org/10.1016/j.str.2025.04.017","url":null,"abstract":"Colibactin, a human microbiome-derived genotoxin, promotes colorectal cancer by damaging the host gut epithelial genomes. While colibactin is synthesized via a hybrid non-ribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) pathway, known as pks or clb, the structural details of its biosynthetic enzymes remain limited, hindering our understanding of its biosynthesis and clinical application. In this study, we report the cryo-EM structures of two colibactin-producing PKS enzymes, ClbC and ClbI, captured in different reaction states using a substrate-mimic crosslinker. Our structural analysis revealed the binding sites of carrier protein (CP) domains of the ClbC and ClbI on their ketosynthase (KS) domains. Further, we identified a novel NRPS-PKS docking interaction between ClbI and its upstream enzyme, ClbH, mediated by the C-terminal peptide ClbH and the dimeric interface of ClbI, establishing a 1:2 stoichiometry. These findings advance our understanding of colibactin assembly line and provide broader insights into NRPS-PKS natural product biosynthesis mechanisms.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"35 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066265","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 comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV 一个全面的工程策略，提高效力和制造近泛中和抗体抗艾滋病毒

IF 5.7 2区生物学

Structure Pub Date : 2025-05-14 DOI: 10.1016/j.str.2025.04.016

Mohammad M. Sajadi, Abdolrahim Abbasi, Zahra Rikhtegaran Tehrani, Christine Siska, Rutilio Clark, Woo Chi, Michael S. Seaman, Dieter Mielke, Kshitij Wagh, Qingbo Liu, Taylor Jumpa, Randal R. Ketchem, Dung N. Nguyen, William D. Tolbert, Brian G. Pierce, Ben Atkinson, Derrick Deming, Megan Sprague, Andrew Asakawa, David Ferrer, Anthony DeVico

{"title":"A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV","authors":"Mohammad M. Sajadi, Abdolrahim Abbasi, Zahra Rikhtegaran Tehrani, Christine Siska, Rutilio Clark, Woo Chi, Michael S. Seaman, Dieter Mielke, Kshitij Wagh, Qingbo Liu, Taylor Jumpa, Randal R. Ketchem, Dung N. Nguyen, William D. Tolbert, Brian G. Pierce, Ben Atkinson, Derrick Deming, Megan Sprague, Andrew Asakawa, David Ferrer, Anthony DeVico","doi":"10.1016/j.str.2025.04.016","DOIUrl":"https://doi.org/10.1016/j.str.2025.04.016","url":null,"abstract":"Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential to prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials with “first-generation” bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of “enhanced” antibodies will be required for optimal clinical utility, while preserving or enhancing Current Good Manufacturing Practices (cGMP) manufacturing capability. Here, we report the engineering of an anti-CD4-binding site (CD4bs) bnAb, N49P9.3. Through a series of rational modifications, we produced a variant, N49P9.6-FR-LS, that demonstrates enhanced potency, superior antiviral activity in combination with other bnAbs, low polyreactivity, and longer circulating half-life. Additional engineering for manufacturing produced a final variant, eN49P9, with properties conducive to cGMP production. Overall, these efforts demonstrate the feasibility of developing enhanced anti-CD4bs bnAbs with greatly improved antiviral properties as well as potential translational value.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"2 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946274","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

Structural insights from active site variants and β-8 loop interactions in viperin-like enzymes 蛇毒样酶活性位点变异和β-8环相互作用的结构见解

IF 5.7 2区生物学

Structure Pub Date : 2025-05-14 DOI: 10.1016/j.str.2025.04.009

Jake C. Lachowicz, Steven Grudman, Jeffrey B. Bonanno, Andras Fiser, Tyler L. Grove

{"title":"Structural insights from active site variants and β-8 loop interactions in viperin-like enzymes","authors":"Jake C. Lachowicz, Steven Grudman, Jeffrey B. Bonanno, Andras Fiser, Tyler L. Grove","doi":"10.1016/j.str.2025.04.009","DOIUrl":"https://doi.org/10.1016/j.str.2025.04.009","url":null,"abstract":"Viperin and viperin-like enzymes (VLEs) are members of the radical SAM superfamily that perform radical-mediated dehydrations on nucleoside triphosphates to yield 3′-deoxy-3′,4′-didehydronucleoside triphosphates (ddhNTPs). Interestingly, viperin and VLEs demonstrate species-dependent substrate selectivity. Some fungal species have a second VLE and, while most viperin and VLEs contain an NΦHX4CX3CX2CF motif, these secondary VLEs are catalytically hindered by a histidine to phenylalanine substitution, an NΦFX4CX3CX2CF motif (NΦF). Herein, we utilize a combination of bioinformatics, enzymology, and X-ray crystallography to demonstrate that NΦF VLEs likely utilize CTP as a substrate. Based on these observations, we demonstrate that the β-8 loop in TvVip1 can be engineered with the β-8 loop from a CTP-selective viperin (Mus musculus) to “swap” substrate selectivity from UTP to CTP. These results provide insight into the determinants of substrate selectivity exhibited by VLEs and introduce a potential route for engineering viperin and VLEs to form alternative ddhNTPs.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"33 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946283","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

Structural and functional interrelationships of histone H2A with its variants H2A.Z and H2A.W in Arabidopsis 组蛋白H2A及其变体H2A的结构和功能相互关系。Z和H2A。W在拟南芥中

IF 5.7 2区生物学

Structure Pub Date : 2025-05-12 DOI: 10.1016/j.str.2025.04.015

Youchao Wang, Jiabing Wu, Shuoming Yang, Xiang Li, Jiachen Wang, Qinghe Lv, Xiaoyu Zhu, Guoliang Lu, Jinru Zhang, Wen-Hui Shen, Bing Liu, Jinzhong Lin, Aiwu Dong

{"title":"Structural and functional interrelationships of histone H2A with its variants H2A.Z and H2A.W in Arabidopsis","authors":"Youchao Wang, Jiabing Wu, Shuoming Yang, Xiang Li, Jiachen Wang, Qinghe Lv, Xiaoyu Zhu, Guoliang Lu, Jinru Zhang, Wen-Hui Shen, Bing Liu, Jinzhong Lin, Aiwu Dong","doi":"10.1016/j.str.2025.04.015","DOIUrl":"https://doi.org/10.1016/j.str.2025.04.015","url":null,"abstract":"Multiple histone H2A variants are known in eukaryotes. However, the functional relationship between H2A and its variants in plants remains largely obscure. Using CRISPR-Cas9 editing, we generated a mutant lacking four H2A isoforms in Arabidopsis and analyzed the functional and structural relationships between H2A, H2A.Z, and H2A.W. RNA sequencing and phenotype analyses revealed mild changes in gene transcription and plant development in mutants lacking H2A, H2A.Z, or H2A.W compared with the wild-type plants. Chromatin immunoprecipitation sequencing analysis showed that H2A can substitute for both H2A.Z and H2A.W across the genome, including in euchromatin and heterochromatin regions. However, H2A.Z replaced both H2A and H2A.W primarily within the euchromatin regions. By using DNA and histones from Arabidopsis, we constructed nucleosomes containing H2A, H2A.Z, or H2A.W and resolved their cryogenic electron microscopy (cryo-EM) structures at near-atomic resolution. Collectively, the results reveal the structural similarity and functional redundancy of H2A and its variants in Arabidopsis.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"1 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933507","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

Structural insights into the human system y+L amino acid transporter complex 人体系统y+L氨基酸转运复合物的结构见解

IF 5.7 2区生物学

Structure Pub Date : 2025-05-09 DOI: 10.1016/j.str.2025.04.012

Lu Dai, Kangtai Xu, Ting Zhang, Xiaoting Wang, Qian Zeng, Hao Liang, Chenye Xu, Liuqing Yang, Zilong Wang, Renhong Yan

{"title":"Structural insights into the human system y+L amino acid transporter complex","authors":"Lu Dai, Kangtai Xu, Ting Zhang, Xiaoting Wang, Qian Zeng, Hao Liang, Chenye Xu, Liuqing Yang, Zilong Wang, Renhong Yan","doi":"10.1016/j.str.2025.04.012","DOIUrl":"https://doi.org/10.1016/j.str.2025.04.012","url":null,"abstract":"System y+L facilitates the sodium-independent transport of cationic and sodium-dependent transport of neutral amino acids via heteromeric amino acid transporters. System y+L consists of either SLC7A6 (y+LAT2) or SLC7A7 (y+LAT1) and 4F2hc (SLC3A2). The y+LAT2-4F2hc complex mediates the exchange of L-lysine (Lys), L-arginine (Arg), L-leucine (Leu), and L-glutamine (Gln) and is important for the glutamate-glutamine cycle and ammonia clearance. c-Myc-driven upregulation of y+LAT2 in cancer enhances amino acid uptake and mTORC1 activation, promoting tumor growth. Its transport mechanism has remained unclear. Here, we determined the cryoelectron microscopic (cryo-EM) structures of the y+LAT2-4F2hc complex bound to either Arg or Leu at 3.60 Å and 3.58 Å resolution, respectively, revealing an outward-open conformation. Our structural analysis highlights conformational changes during transport, and functional assays validate critical residues involved in substrate binding and transport. These findings elucidate the molecular mechanism of the system y+L and provide a foundation for developing targeted therapies against y+LAT2.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"20 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926679","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

Sla2 is a core interaction hub for clathrin light chain and the Pan1/End3/Sla1 complex Sla2是网格蛋白轻链和Pan1/End3/Sla1复合物相互作用的核心枢纽

IF 5.7 2区生物学

Structure Pub Date : 2025-05-09 DOI: 10.1016/j.str.2025.04.013

George Draper-Barr, Lucas A. Defelipe, David Ruiz-Carrillo, Emil Gustavsson, Meytal Landau, Maria García-Alai

引用次数: 0