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Automated fiducial-based alignment of cryo-electron tomography tilt series in Dynamo 在 Dynamo 中基于靶标自动对准低温电子断层扫描倾斜序列
IF 5.7 2区 生物学
Structure Pub Date : 2024-07-29 DOI: 10.1016/j.str.2024.07.003
{"title":"Automated fiducial-based alignment of cryo-electron tomography tilt series in Dynamo","authors":"","doi":"10.1016/j.str.2024.07.003","DOIUrl":"https://doi.org/10.1016/j.str.2024.07.003","url":null,"abstract":"<p>With the advent of modern technologies for cryo-electron tomography (cryo-ET), high-quality tilt series are more rapidly acquired than processed and analyzed. Thus, a robust and fast-automated alignment for batch processing in cryo-ET is needed. While different software packages have made available several approaches for automated marker-based alignment of tilt series, manual user intervention remains necessary for many datasets, thus preventing high-throughput tomography.</p><p>We have developed a MATLAB-based framework integrated into the Dynamo software package for automatic detection of fiducial markers that generates a robust alignment model with minimal input parameters. This approach allows high-throughput, unsupervised volume reconstruction. This new module extends Dynamo with a large repertory of tools for tomographic alignment and reconstruction, as well as specific visualization browsers to rapidly assess the biological relevance of the dataset. Our approach has been successfully tested on a broad range of datasets that include diverse biological samples and cryo-ET modalities.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141795031","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 of phage transcriptional regulation 噬菌体转录调控的结构基础
IF 5.7 2区 生物学
Structure Pub Date : 2024-07-26 DOI: 10.1016/j.str.2024.07.002
{"title":"Structural basis of phage transcriptional regulation","authors":"","doi":"10.1016/j.str.2024.07.002","DOIUrl":"https://doi.org/10.1016/j.str.2024.07.002","url":null,"abstract":"<p>Phages are the most prevalent and diverse entities in the biosphere and represent the simplest systems that are capable of self-replication. Many fundamental concepts of transcriptional regulation were revealed through phage studies. The replication of phages within bacteria entails the hijacking of the host transcription machinery. Typically, this is accomplished through proteins and RNAs encoded by the phage genome that bind to the host RNA polymerase and modify its characteristics. Understanding these processes offers valuable insights into the mechanisms of bacterial transcription itself. Historically, X-ray crystallography has been the major tool for elucidating the structural basis of phage transcriptional regulation. In recent years, the application of cryoelectron microscopy has not only allowed the exploration of protein-protein and protein-nucleic acid interactions at near-atomic resolution but also captured transient intermediate states, further expanding our mechanistic understanding of phage transcriptional regulation.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764459","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 inhibition of βFXIIa by garadacimab 加拉地单抗抑制 βFXIIa 的结构基础
IF 5.7 2区 生物学
Structure Pub Date : 2024-07-25 DOI: 10.1016/j.str.2024.07.001
{"title":"Structural basis for the inhibition of βFXIIa by garadacimab","authors":"","doi":"10.1016/j.str.2024.07.001","DOIUrl":"https://doi.org/10.1016/j.str.2024.07.001","url":null,"abstract":"<p>Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of βFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754352","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 mechanism of the endothelin receptor type B interactions with Gs, Gi, and Gq B 型内皮素受体与 Gs、Gi 和 Gq 相互作用的分子机制
IF 5.7 2区 生物学
Structure Pub Date : 2024-07-22 DOI: 10.1016/j.str.2024.06.020
{"title":"Molecular mechanism of the endothelin receptor type B interactions with Gs, Gi, and Gq","authors":"","doi":"10.1016/j.str.2024.06.020","DOIUrl":"https://doi.org/10.1016/j.str.2024.06.020","url":null,"abstract":"<p>The endothelin receptor type B (ET<sub>B</sub>) exhibits promiscuous coupling with various heterotrimeric G protein subtypes including Gs, Gi/o, Gq/11, and G12/13. Recent fluorescence and structural studies have raised questions regarding the coupling efficiencies and determinants of these G protein subtypes. Herein, by utilizing an integrative approach, combining hydrogen/deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cellular systems, we investigated conformational changes of Gs, Gi, and Gq triggered by ET<sub>B</sub> activation. ET<sub>B</sub> coupled to Gi and Gq but not with Gs. We underscored the critical roles of specific regions, including the C terminus of Gα and intracellular loop 2 (ICL2) of ET<sub>B</sub> in ET<sub>B</sub>-Gi1 or ET<sub>B</sub>-Gq coupling. Although The C terminus of Gα is essential for ET<sub>B</sub>-Gi1 and ET<sub>B</sub>-Gq coupling, ET<sub>B</sub> ICL2 influences Gq-coupling but not Gi1-coupling. Our results suggest a differential coupling efficiency of ET<sub>B</sub> with Gs, Gi1, and Gq, accompanied by distinct conformational changes in G proteins upon ET<sub>B</sub>-induced activation.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141746577","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
Intracellular tau fragment droplets serve as seeds for tau fibrils 细胞内的 tau 片段小滴是 tau 纤维的种子
IF 5.7 2区 生物学
Structure Pub Date : 2024-07-19 DOI: 10.1016/j.str.2024.06.018
{"title":"Intracellular tau fragment droplets serve as seeds for tau fibrils","authors":"","doi":"10.1016/j.str.2024.06.018","DOIUrl":"https://doi.org/10.1016/j.str.2024.06.018","url":null,"abstract":"<p>Intracellular tau aggregation requires a local protein concentration increase, referred to as “droplets”. However, the cellular mechanism for droplet formation is poorly understood. Here, we expressed OptoTau, a P301L mutant tau fused with CRY2olig, a light-sensitive protein that can form homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment suggesting that intracellular tau droplet formation requires microtubule collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau observed in the Alzheimer’s disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm with blue light stimulation. These intracellular stable tau clusters acted as a seed for tau fibrils <em>in vitro</em>. These results suggest that tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726361","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 assembly pathway of the Helicobacter pylori CagT4SS outer membrane core complex 幽门螺杆菌 CagT4SS 外膜核心复合物组装途径的结构启示
IF 5.7 2区 生物学
Structure Pub Date : 2024-07-19 DOI: 10.1016/j.str.2024.06.019
{"title":"Structural insights into the assembly pathway of the Helicobacter pylori CagT4SS outer membrane core complex","authors":"","doi":"10.1016/j.str.2024.06.019","DOIUrl":"https://doi.org/10.1016/j.str.2024.06.019","url":null,"abstract":"<p>Cag type IV secretion system (CagT4SS) translocates oncoprotein cytotoxin-associated gene A (CagA) into host cells and plays a key role in the pathogenesis of <em>Helicobacter pylori</em>. The structure of the outer membrane core complex (OMCC) in CagT4SS consists of CagX, CagY, CagM, CagT, and Cag3 in a stoichiometric ratio of 1:1:2:2:5 with 14-fold symmetry. However, the assembly pathway of OMCC remains elusive. Here, we report the crystal structures of CagT and Cag3-CagT complex, and the structural dynamics of Cag3 and CagT using hydrogen deuterium exchange-mass spectrometry (HDX-MS). The interwoven interaction of Cag3 and CagT involves conformational changes of CagT and β strand swapping. In conjunction with biochemical and biophysical assays, we further demonstrate the different oligomerization states of Cag3 and Cag3-CagT complex. Additionally, the association with CagM requires the pre-formation of Cag3-CagT complex. These results demonstrate the generation of different intermediate sub-assemblies and their structural flexibility, potentially representing different building blocks for OMCC assembly.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726356","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 an atypical histone binding mechanism by a PHD finger 从结构上揭示 PHD 指的非典型组蛋白结合机制
IF 5.7 2区 生物学
Structure Pub Date : 2024-07-18 DOI: 10.1016/j.str.2024.06.017
{"title":"Structural insights into an atypical histone binding mechanism by a PHD finger","authors":"","doi":"10.1016/j.str.2024.06.017","DOIUrl":"https://doi.org/10.1016/j.str.2024.06.017","url":null,"abstract":"<p>Complex associating with SET1 (COMPASS) is a histone H3K4 tri-methyltransferase controlled by several regulatory subunits including CXXC zinc finger protein 1 (Cfp1). Prior studies established the structural underpinnings controlling H3K4me3 recognition by the PHD domain of Cfp1’s yeast homolog (Spp1). However, metazoans Cfp1<sup>PHD</sup> lacks structural elements important for H3K4me3 stabilization in Spp1, suggesting that in metazoans, Cfp1<sup>PHD</sup> domain binds H3K4me3 differently. The structure of Cfp1<sup>PHD</sup> in complex with H3K4me3 shows unique features such as non-canonical coordination of the first zinc atom and a disulfide bond forcing the reorientation of Cfp1<sup>PHD</sup> N-terminus, thereby leading to an atypical H3K4me3 binding pocket. This configuration minimizes Cfp1<sup>PHD</sup> reliance on canonical residues important for histone binding functions of other PHD domains. Cancer-related mutations in Cfp1<sup>PHD</sup> impair H3K4me3 binding, implying a potential impact on epigenetic signaling. Our work highlights a potential diversification of PHD histone binding modes and the impact of cancer mutations on Cfp1 functions.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726369","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
Cryo-EM structures reveal the molecular mechanism of HflX-mediated erythromycin resistance in mycobacteria 低温电子显微镜结构揭示了分枝杆菌中 HflX 介导的红霉素抗药性的分子机制
IF 5.7 2区 生物学
Structure Pub Date : 2024-07-18 DOI: 10.1016/j.str.2024.06.016
{"title":"Cryo-EM structures reveal the molecular mechanism of HflX-mediated erythromycin resistance in mycobacteria","authors":"","doi":"10.1016/j.str.2024.06.016","DOIUrl":"https://doi.org/10.1016/j.str.2024.06.016","url":null,"abstract":"<p>Mycobacterial HflX confers resistance against macrolide antibiotics. However, the exact molecular mechanism is poorly understood. To gain further insights, we determined the cryo-EM structures of <em>M. smegmatis</em> (Msm) HflX-50S subunit and 50S subunit-erythromycin (ERY) complexes at a global resolution of approximately 3 Å. A conserved nucleotide A2286 at the gate of nascent peptide exit tunnel (NPET) adopts a swayed conformation in HflX-50S complex and interacts with a loop within the linker helical (LH) domain of MsmHflX that contains an additional 9 residues insertion. Interestingly, the swaying of this nucleotide, which is usually found in the non-swayed conformation, is induced by erythromycin binding. Furthermore, we observed that erythromycin decreases HflX’s ribosome-dependent GTP hydrolysis, resulting in its enhanced binding and anti-association activity on the 50S subunit. Our findings reveal how mycobacterial HflX senses the presence of macrolides at the peptide tunnel entrance and confers antibiotic resistance in mycobacteria.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726362","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
They all rock: A systematic comparison of conformational movements in LeuT-fold transporters 它们都很震撼对LeuT折叠转运体构象移动的系统比较
IF 5.7 2区 生物学
Structure Pub Date : 2024-07-17 DOI: 10.1016/j.str.2024.06.015
{"title":"They all rock: A systematic comparison of conformational movements in LeuT-fold transporters","authors":"","doi":"10.1016/j.str.2024.06.015","DOIUrl":"https://doi.org/10.1016/j.str.2024.06.015","url":null,"abstract":"<p>Many membrane transporters share the LeuT fold—two five-helix repeats inverted across the membrane plane. Despite hundreds of structures, whether distinct conformational mechanisms are supported by the LeuT fold has not been systematically determined. After annotating published LeuT-fold structures, we analyzed distance difference matrices (DDMs) for nine proteins with multiple available conformations. We identified rigid bodies and relative movements of transmembrane helices (TMs) during distinct steps of the transport cycle. In all transporters, the bundle (first two TMs of each repeat) rotates relative to the hash (third and fourth TMs). Motions of the arms (fifth TM) to close or open the intracellular and outer vestibules are common, as is a TM1a swing, with notable variations in the opening-closing motions of the outer vestibule. Our analyses suggest that LeuT-fold transporters layer distinct motions on a common bundle-hash rock and demonstrate that systematic analyses can provide new insights into large structural datasets.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141631799","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
Berberine analog of chloramphenicol exhibits a distinct mode of action and unveils ribosome plasticity 氯霉素的小檗碱类似物显示出独特的作用模式并揭示了核糖体的可塑性
IF 5.7 2区 生物学
Structure Pub Date : 2024-07-16 DOI: 10.1016/j.str.2024.06.013
{"title":"Berberine analog of chloramphenicol exhibits a distinct mode of action and unveils ribosome plasticity","authors":"","doi":"10.1016/j.str.2024.06.013","DOIUrl":"https://doi.org/10.1016/j.str.2024.06.013","url":null,"abstract":"<p>Chloramphenicol (CHL) is an antibiotic targeting the peptidyl transferase center in bacterial ribosomes. We synthesized a new analog, CAM-BER, by substituting the dichloroacetyl moiety of CHL with a positively charged aromatic berberine group. CAM-BER suppresses bacterial cell growth, inhibits protein synthesis <em>in vitro</em>, and binds tightly to the 70S ribosome. Crystal structure analysis reveals that the bulky berberine group folds into the P site of the peptidyl transferase center (PTC), where it competes with the formyl-methionine residue of the initiator tRNA. Our toe-printing data confirm that CAM-BER acts as a translation initiation inhibitor in stark contrast to CHL, a translation elongation inhibitor. Moreover, CAM-BER induces a distinct rearrangement of conformationally restrained nucleotide A2059, suggesting that the 23S rRNA plasticity is significantly higher than previously thought. CAM-BER shows potential in avoiding CHL resistance and presents opportunities for developing novel berberine derivatives of CHL through medicinal chemistry exploration.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625174","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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