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RQC2 is a major player in peptide release from stalled ribosomes
IF 5.7 2区 生物学
Structure Pub Date : 2025-04-04 DOI: 10.1016/j.str.2025.03.008
Céline Fabret, Emmanuel Giudice, Sophie Chat, Reynald Gillet, Olivier Namy
{"title":"RQC2 is a major player in peptide release from stalled ribosomes","authors":"Céline Fabret, Emmanuel Giudice, Sophie Chat, Reynald Gillet, Olivier Namy","doi":"10.1016/j.str.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.str.2025.03.008","url":null,"abstract":"Eukaryotic cells prevent the accumulation of potentially toxic aberrant polypeptides and maintain ribosome availability through surveillance and clearance mechanisms, including the evolutionarily conserved ribosome-associated quality control complex (RQC). RQC pathways have been widely investigated, with the identification of several factors ANKZF1/Vms1p, Ptrh1, and Arb1p involved in release/cleavage of the peptide-tRNA from 60S subunits. We aimed here to identify the genes involved in peptide release from stalled ribosomes. Using a genetic screen, we identified a mutant allele of <em>RQC2</em> as involved in this process. We present the cryoelectron microscopy (cryo-EM) structure of RQC, which reveals how the F340I mutation affects mutant binding. This altered binding, in turn, disrupts the A-site’s ability to bind the tRNA in the presence of Ltn1. These data account for the limitation of C-terminal alanine and threonine (CAT) tailing by the F340I mutation and suggest a model explaining the role of the Rqc2 protein in peptide release.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"73 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775923","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 tale of detergent tails: GPCR activation beyond ligands
IF 5.7 2区 生物学
Structure Pub Date : 2025-04-03 DOI: 10.1016/j.str.2025.03.005
Eugene Agyemang, Rajan Lamichhane
{"title":"A tale of detergent tails: GPCR activation beyond ligands","authors":"Eugene Agyemang, Rajan Lamichhane","doi":"10.1016/j.str.2025.03.005","DOIUrl":"https://doi.org/10.1016/j.str.2025.03.005","url":null,"abstract":"In this issue of <em>Structure</em>, Banerjee et al.<span><span><sup>1</sup></span></span> use single-molecule FRET to explore how various detergents and cholesterol influence the conformational dynamics of the extracellular domain of the metabotropic glutamate receptor 2 (mGluR2). They show that the local membrane environment modulates the receptor’s active-inactive state equilibrium and identifies specific cholesterol-binding sites, offering insights into potential drug-targeting strategies for mGluR2.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"33 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766774","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
Spy-ing on nucleic acids: Atomic resolution of the S. pyogenes CRISPR-Cas9 surveillance state
IF 5.7 2区 生物学
Structure Pub Date : 2025-04-03 DOI: 10.1016/j.str.2025.03.001
Alexa L. Knight, George P. Lisi
{"title":"Spy-ing on nucleic acids: Atomic resolution of the S. pyogenes CRISPR-Cas9 surveillance state","authors":"Alexa L. Knight, George P. Lisi","doi":"10.1016/j.str.2025.03.001","DOIUrl":"https://doi.org/10.1016/j.str.2025.03.001","url":null,"abstract":"In a recent issue of <em>Cell Chemical Biology</em>, De Paula et al.<span><span><sup>1</sup></span></span> report an extensive methyl-TROSY solution NMR study of the CRISPR-Cas9 holoenzyme. Studying millisecond-to-second protein dynamics using individual domain constructs of Cas9 coupled to structural interrogations of the full-length enzyme, the authors describe the Cas9 “surveillance state,” a molecular mechanism driving the discrimination between on- and off-target DNA.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"58 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766829","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 the Staphylococcus aureus bacteriophage 80α neck shows details of the DNA, tail completion protein, and tape measure protein
IF 5.7 2区 生物学
Structure Pub Date : 2025-04-01 DOI: 10.1016/j.str.2025.03.007
James L. Kizziah, Amarshi Mukherjee, Laura K. Parker, Terje Dokland
{"title":"Structure of the Staphylococcus aureus bacteriophage 80α neck shows details of the DNA, tail completion protein, and tape measure protein","authors":"James L. Kizziah, Amarshi Mukherjee, Laura K. Parker, Terje Dokland","doi":"10.1016/j.str.2025.03.007","DOIUrl":"https://doi.org/10.1016/j.str.2025.03.007","url":null,"abstract":"The <em>Staphylococcus aureus</em> pathogenicity islands (SaPIs), including SaPI1, are a type of mobile genetic elements (MGEs) that are mobilized at high frequency by “helper” bacteriophages, such as 80α, leading to packaging of the SaPI genomes into virions made from helper-encoded structural proteins. 80α and SaPI1 virions consist of an icosahedral head connected via a portal vertex to a long, non-contractile tail. A connector or “neck” forms the interface between the tail and the head. Here, we have determined the high-resolution structure of the neck section of SaPI1 virions, including the dodecameric portal and head-tail-connector proteins, and the hexameric head-tail joining, tail terminator and major tail proteins. We also resolved the DNA, the tail completion protein (TCP), and the tape measure protein (TMP) inside the tail, features that have not previously been observed at high resolution. Our study provides insights into the assembly and infection process in this important group of MGEs.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"28 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745605","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
Disulfide-stabilized diabodies enable near-atomic cryo-EM imaging of small proteins: A case study of the bacterial Na+/citrate symporter CitS
IF 5.7 2区 生物学
Structure Pub Date : 2025-03-31 DOI: 10.1016/j.str.2025.03.006
Subin Kim, Ji Won Kim, Jun Gyou Park, Sang Soo Lee, Seung Hun Choi, Jie-Oh Lee, Mi Sun Jin
{"title":"Disulfide-stabilized diabodies enable near-atomic cryo-EM imaging of small proteins: A case study of the bacterial Na+/citrate symporter CitS","authors":"Subin Kim, Ji Won Kim, Jun Gyou Park, Sang Soo Lee, Seung Hun Choi, Jie-Oh Lee, Mi Sun Jin","doi":"10.1016/j.str.2025.03.006","DOIUrl":"https://doi.org/10.1016/j.str.2025.03.006","url":null,"abstract":"Diabodies are engineered antibody fragments with two antigen-binding Fv domains. Previously, we demonstrated that they are often highly flexible but can be rigidified by introducing a disulfide bond at the Fv interface. In this study, we explored the potential of disulfide-bridged, bispecific diabodies for near-atomic cryoelectron microscopy (cryo-EM) imaging of small proteins because they can predictably link target proteins to “structural marker” proteins. As a case study, we used the bacterial citrate transporter CitS as the target protein, and the horseshoe-shaped ectodomain of human Toll-like receptor 3 (TLR3) as the marker. We show that diabodies containing one or two disulfide bonds enabled the 3D reconstruction of CitS at resolutions of 3.3 Å and 3.1 Å, respectively. This resolution surpassed previous crystallographic results and allowed us to visualize the high-resolution structural features of the transporter. Our work expands the application of diabodies in structural biology to address a key limitation in the field.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"56 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736968","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
ATP binding controls the molecular function of bacterial MutS2 by mediating closure of the dimeric clamp structure
IF 5.7 2区 生物学
Structure Pub Date : 2025-03-28 DOI: 10.1016/j.str.2025.03.003
Kenji Fukui, Takeshi Murakawa, Nobumasa Hino, Naoyuki Kondo, Takato Yano
{"title":"ATP binding controls the molecular function of bacterial MutS2 by mediating closure of the dimeric clamp structure","authors":"Kenji Fukui, Takeshi Murakawa, Nobumasa Hino, Naoyuki Kondo, Takato Yano","doi":"10.1016/j.str.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.str.2025.03.003","url":null,"abstract":"MutS2 recognizes branched DNA structures to regulate homologous recombination. MutS2 also has a role in ribosome recycling, where it resolves collided ribosomes. These functions require ATP-dependent conformational changes of MutS2. In the known nucleotide-free and ADP-bound MutS2 structures the dimeric clamp-like structure adopts open conformations. Here, we present the crystal structure of MutS2 with a bound ATP analog revealing a closed conformation of the clamp. Experiments with MutS2, where an unnatural photo-crosslinking capable amino acid was introduced into the clamp revealed that ATP-dependent closure also occurs in solution. Binding of MutS2 to a terminal-containing DNA was not affected by ATP, whereas that to a terminal-less DNA was reinforced. These findings suggest that clamp closure enables MutS2 to stay bound to recombination intermediates, which might regulate recombination. Furthermore, closure of the clamp provides insights into the mechanism of dissociation of collided ribosomes mediated by MutS2.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"21 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723813","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 basis for the constitutive activity of the melanocortin receptor family
IF 5.7 2区 生物学
Structure Pub Date : 2025-03-28 DOI: 10.1016/j.str.2025.03.004
Wenbo Feng, Qingtong Zhou, Chang Zheng, Dehua Yang, Ming-Wei Wang
{"title":"Structural basis for the constitutive activity of the melanocortin receptor family","authors":"Wenbo Feng, Qingtong Zhou, Chang Zheng, Dehua Yang, Ming-Wei Wang","doi":"10.1016/j.str.2025.03.004","DOIUrl":"https://doi.org/10.1016/j.str.2025.03.004","url":null,"abstract":"The constitutive activity of melanocortin receptors (MCRs) is integral to several physiological processes. The unliganded cryo-electron microscopy structures of MC1R, MC2R, MC3R, MC4R, and MC5R in complex with G<sub>s</sub> proteins determined at global resolutions of 2.98 Å, 3.01 Å, 2.75 Å, 3.12 Å, and 2.86 Å, respectively, revealed that their binding poses and interactions with G<sub>s</sub> are similar to those of agonist-bound MCRs. The extracellular regions of the transmembrane helices (TMs) exhibit distinct conformational rearrangements, characterized by varying shifts of TM3 and outward displacements of TM4. These variations represent unique structural features of constitutively activated MCRs. Unassigned electron densities were observed within the orthosteric pockets where extensive interactions with cognate ligands occur. In addition, zinc ions, but not calcium, positively regulated MC4R activity in a dose-dependent manner. Our findings provide valuable insights into the molecular mechanisms underlying MCR basal activity and highlight the role of divalent ions in receptor activation.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"215 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723812","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 mesophilic Argonaute from Clostridium formicaceticum with efficient DNA cleavage activity guided by small DNA
IF 5.7 2区 生物学
Structure Pub Date : 2025-03-28 DOI: 10.1016/j.str.2025.03.002
Jianrui Li, Meixia Yu, Zhijia Yang, Yueheng Zhou, Yunpeng Teng, Zijian Wang, Jian Chen, Jinsheng Lai, Beibei Xin
{"title":"A mesophilic Argonaute from Clostridium formicaceticum with efficient DNA cleavage activity guided by small DNA","authors":"Jianrui Li, Meixia Yu, Zhijia Yang, Yueheng Zhou, Yunpeng Teng, Zijian Wang, Jian Chen, Jinsheng Lai, Beibei Xin","doi":"10.1016/j.str.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.str.2025.03.002","url":null,"abstract":"We characterized a new Argonaute protein (pAgo), <em>Cf</em>Ago, from the mesophilic bacterium <em>Clostridium formicaceticum</em>. <em>Cf</em>Ago possesses DNA-guided DNA endonuclease activity and cleaves DNA targets at the canonical site. It is active from 28°C to 75°C and prefers DNA guides with a 5′-phosphate group and thymidine as the first nucleotide. Cleavage activity is reduced by single-nucleotide mismatches in the seed, central, and 3′-supplementary regions of guides, with stronger mismatch discrimination observed for 5′hydroxylated (5′OH) guides compared to 5′phosphorylated (5′P) guides. Moreover, structural analysis suggests that the MID domain of <em>Cf</em>Ago is crucial for recognizing the 5′ guide and it influences the binding specificity. <em>Cf</em>Ago catalyzes programmable cleavage of double-stranded DNA in AT-rich regions in the presence of Mn<sup>2+</sup> and Mg<sup>2+</sup> ions at appropriate salt concentrations. These properties could make <em>Cf</em>Ago a promising tool for DNA manipulation such as nucleic acid detection and cleavage.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"15 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723814","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
Structurally diverse C-terminal accessory domains in type I ABC importers reveal distinct regulatory mechanisms
IF 5.7 2区 生物学
Structure Pub Date : 2025-03-24 DOI: 10.1016/j.str.2025.02.014
Evan R. Buechel, Valentina S. Dimitrova, Alexandra Karagiaridi, Lydia G. Kenney, Heather W. Pinkett
{"title":"Structurally diverse C-terminal accessory domains in type I ABC importers reveal distinct regulatory mechanisms","authors":"Evan R. Buechel, Valentina S. Dimitrova, Alexandra Karagiaridi, Lydia G. Kenney, Heather W. Pinkett","doi":"10.1016/j.str.2025.02.014","DOIUrl":"https://doi.org/10.1016/j.str.2025.02.014","url":null,"abstract":"ATP-binding cassette (ABC) transporters are critical for cellular processes, facilitating the transport of various substrates across membranes by harnessing ATP hydrolysis. These transporters are divided into importers and exporters, with importers playing key roles in nutrient uptake and bacterial virulence. Despite their therapeutic potential as drug targets, the regulatory mechanisms governing ABC importers remain poorly understood. ABC importers often possess additional cytosolic C-terminal accessory domains fused to nucleotide-binding domains (NBDs). These accessory domains, also referred to as C-terminal regulatory domains (CRDs), modulate transport activity by inhibiting NBD dimerization or ATP hydrolysis in response to environmental cues, thus regulating substrate transport. The diversity in CRD folds, architectures, and regulatory mechanisms adds additional complexity to transporter regulation. This review explores the current understanding of C-terminal accessory domains in type I ABC importers, highlighting their contributions to transporter function.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"59 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677857","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 structural perspective on the temperature dependent activity of enzymes
IF 5.7 2区 生物学
Structure Pub Date : 2025-03-21 DOI: 10.1016/j.str.2025.02.013
Matthew J. McLeod, Sarah A.E. Barwell, Todd Holyoak, Robert E. Thorne
{"title":"A structural perspective on the temperature dependent activity of enzymes","authors":"Matthew J. McLeod, Sarah A.E. Barwell, Todd Holyoak, Robert E. Thorne","doi":"10.1016/j.str.2025.02.013","DOIUrl":"https://doi.org/10.1016/j.str.2025.02.013","url":null,"abstract":"Enzyme activity varies with temperature. Unlike small-molecule catalysts, the structural ensembles of enzymes can change substantially with temperature, but it is unclear how this modulates temperature dependent activity. Here, multi-temperature X-ray crystallography was used to record structural changes from ˗20°C to 40°C for a mesophilic enzyme in complex with inhibitors mimicking substrate-, intermediate-, and product-bound states, representative of major complexes on the reaction coordinate. Inhibitors, substrates and active site loops increasingly populated catalytically competent conformations as temperature increased. These changes occurred even in temperature ranges where kinetic measurements showed roughly linear Arrhenius/Eyring behavior, where parameters characterizing the system are assumed to be temperature independent. Simple analysis shows that linear Arrhenius/Eyring behavior can still be observed when the underlying activation energy/enthalpy values vary with temperature. Our results indicate a critical role for temperature dependent atomic-resolution structural data in interpreting temperature dependent kinetic data from enzymatic systems.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"56 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666284","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
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