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Insights into the distinct membrane targeting mechanisms of WDR91 family proteins 深入了解 WDR91 家族蛋白的不同膜靶向机制
IF 5.7 2区 生物学
Structure Pub Date : 2024-10-18 DOI: 10.1016/j.str.2024.09.023
Xinli Ma, Jian Li, Nan Liu, Surajit Banerjee, Xiaotong Hu, Xiaoyu Wang, Jianshu Dong, Kangdong Liu, Chonglin Yang, Zigang Dong
{"title":"Insights into the distinct membrane targeting mechanisms of WDR91 family proteins","authors":"Xinli Ma, Jian Li, Nan Liu, Surajit Banerjee, Xiaotong Hu, Xiaoyu Wang, Jianshu Dong, Kangdong Liu, Chonglin Yang, Zigang Dong","doi":"10.1016/j.str.2024.09.023","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.023","url":null,"abstract":"WDR91 and SORF1, members of the WD repeat-containing protein 91 family, control phosphoinositide conversion by inhibiting phosphatidylinositol 3-kinase activity on endosomes, which promotes endosome maturation. Here, we report the crystal structure of the human WDR91 WD40 domain complexed with Rab7 that has an unusual interface at the C-terminus of the Rab7 switch II region. WDR91 is highly selective for Rab7 among the tested GTPases. A LIS1 homology (LisH) motif within the WDR91 N-terminal domain (NTD) mediates self-association and may contribute partly to the augmented interaction between full-length WDR91 and Rab7. Both the Rab7 binding site and the LisH motif are indispensable for WDR91 function in endocytic trafficking. For the WDR91 orthologue SORF1 lacking the C-terminal WD40 domain, a C-terminal amphipathic helix (AH) mediates strong interactions with liposomes containing acidic lipids. During evolution the human WDR91 ancestor gene might have acquired a WD40 domain to replace the AH for endosomal membrane targeting.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448832","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 DNA-binding mechanism of BCL11A: The integral role of ZnF6 对 BCL11A DNA 结合机制的结构性认识:ZnF6 的重要作用
IF 5.7 2区 生物学
Structure Pub Date : 2024-10-17 DOI: 10.1016/j.str.2024.09.022
Thibault Viennet, Maolu Yin, Abhilash Jayaraj, Woojin Kim, Zhen-Yu J. Sun, Yuko Fujiwara, Kevin Zhang, Davide Seruggia, Hyuk-Soo Seo, Sirano Dhe-Paganon, Stuart H. Orkin, Haribabu Arthanari
{"title":"Structural insights into the DNA-binding mechanism of BCL11A: The integral role of ZnF6","authors":"Thibault Viennet, Maolu Yin, Abhilash Jayaraj, Woojin Kim, Zhen-Yu J. Sun, Yuko Fujiwara, Kevin Zhang, Davide Seruggia, Hyuk-Soo Seo, Sirano Dhe-Paganon, Stuart H. Orkin, Haribabu Arthanari","doi":"10.1016/j.str.2024.09.022","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.022","url":null,"abstract":"The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: α<sub>2</sub>γ<sub>2</sub>) to adult hemoglobin (HbA: α<sub>2</sub>β<sub>2</sub>) during development. BCL11A binds at a cognate recognition site (TGACCA) in the γ-globin gene promoter and represses its expression. DNA-binding is mediated by a triple zinc finger domain, designated ZnF456. Here, we report comprehensive investigation of ZnF456, leveraging X-ray crystallography and NMR to determine the structures in both the presence and absence of DNA. We delve into the dynamics and mode of interaction with DNA. Moreover, we discovered that the last zinc finger of BCL11A (ZnF6) plays a different role compared to ZnF4 and 5, providing a positive entropic contribution to DNA binding and γ-globin gene repression. Comprehending the DNA binding mechanism of BCL11A opens avenues for the strategic, structure-based design of novel therapeutics targeting sickle cell disease and β-thalassemia.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444185","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
ATTRv-V30M amyloid fibrils from heart and nerves exhibit structural homogeneity 来自心脏和神经的 ATTRv-V30M 淀粉样蛋白纤维在结构上具有同质性
IF 5.7 2区 生物学
Structure Pub Date : 2024-10-17 DOI: 10.1016/j.str.2024.09.021
Binh An Nguyen, Shumaila Afrin, Anna Yakubovska, Virender Singh, Rose Pedretti, Parker Bassett, Maja Pekala, Jaime Vaquer Alicea, Peter Kunach, Lanie Wang, Andrew Lemoff, Barbara Kluve-Beckerman, Lorena Saelices
{"title":"ATTRv-V30M amyloid fibrils from heart and nerves exhibit structural homogeneity","authors":"Binh An Nguyen, Shumaila Afrin, Anna Yakubovska, Virender Singh, Rose Pedretti, Parker Bassett, Maja Pekala, Jaime Vaquer Alicea, Peter Kunach, Lanie Wang, Andrew Lemoff, Barbara Kluve-Beckerman, Lorena Saelices","doi":"10.1016/j.str.2024.09.021","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.021","url":null,"abstract":"Amyloidogenic transthyretin (ATTR) amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin. Transthyretin is primarily produced in tetrameric form by the liver, but also by retinal epithelium and choroid plexus. The deposition of these fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryoelectron microscopy (cryo-EM), we investigated fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found consistent fibril structures from both tissues, similar to cardiac fibrils previously described, but different from vitreous humor fibrils of the same genotype. Our findings, along with previous ATTR fibrils structural studies, suggest a uniform fibrillar architecture across different tissues when transthyretin originates from the liver. This study advances our understanding of how deposition and production sites influence fibril structure in ATTRv-V30M amyloidosis.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444186","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
Ribosome-inactivation by a class of widely distributed C-tail anchored membrane proteins 一类广泛分布的 C 尾锚定膜蛋白的核糖体失活作用
IF 5.7 2区 生物学
Structure Pub Date : 2024-10-16 DOI: 10.1016/j.str.2024.09.019
Robert Karari Njenga, Julian Boele, Friedel Drepper, Kasturica Sinha, Eirini Marouda, Pitter F. Huesgen, Crysten Blaby-Haas, Hans-Georg Koch
{"title":"Ribosome-inactivation by a class of widely distributed C-tail anchored membrane proteins","authors":"Robert Karari Njenga, Julian Boele, Friedel Drepper, Kasturica Sinha, Eirini Marouda, Pitter F. Huesgen, Crysten Blaby-Haas, Hans-Georg Koch","doi":"10.1016/j.str.2024.09.019","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.019","url":null,"abstract":"Ribosome hibernation is a commonly used strategy that protects ribosomes under unfavorable conditions and regulates developmental processes. Multiple ribosome-hibernation factors have been identified in all domains of life, but due to their structural diversity and the lack of a common inactivation mechanism, it is currently unknown how many different hibernation factors exist. Here, we show that the YqjD/ElaB/YgaM paralogs, initially discovered as membrane-bound ribosome binding proteins in <em>E. coli</em>, constitute an abundant class of ribosome-hibernating proteins, which are conserved across all proteobacteria and some other bacterial phyla. Our data demonstrate that they inhibit <em>in vitro</em> protein synthesis by interacting with the 50S ribosomal subunit. <em>In vivo</em> cross-linking combined with mass spectrometry revealed their specific interactions with proteins surrounding the ribosomal tunnel exit and even their penetration into the ribosomal tunnel. Thus, YqjD/ElaB/YgaM inhibit translation by blocking the ribosomal tunnel and thus mimic the activity of antimicrobial peptides and macrolide antibiotics.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440034","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 requirements for the specific binding of CRABP2 to cyclin D3 CRABP2 与细胞周期蛋白 D3 特异性结合的结构要求
IF 5.7 2区 生物学
Structure Pub Date : 2024-10-16 DOI: 10.1016/j.str.2024.09.020
Martyna W. Pastok, Charles W.E. Tomlinson, Shannon Turberville, Abbey M. Butler, Arnaud Baslé, Martin E.M. Noble, Jane A. Endicott, Ehmke Pohl, Natalie J. Tatum
{"title":"Structural requirements for the specific binding of CRABP2 to cyclin D3","authors":"Martyna W. Pastok, Charles W.E. Tomlinson, Shannon Turberville, Abbey M. Butler, Arnaud Baslé, Martin E.M. Noble, Jane A. Endicott, Ehmke Pohl, Natalie J. Tatum","doi":"10.1016/j.str.2024.09.020","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.020","url":null,"abstract":"Cellular retinoic acid binding protein 2 (CRABP2) transports retinoic acid from the cytoplasm to the nucleus where it then transfers its cargo to retinoic acid receptor-containing complexes leading to activation of gene transcription. We demonstrate using purified proteins that CRABP2 is also a cyclin D3-specific binding protein and that the CRABP2 cyclin D3 binding site and the proposed CRABP2 nuclear localization sequence overlap. Both sequences are within the helix-loop-helix motif that forms a lid to the retinoic acid binding pocket. Mutations within this sequence that block both cyclin D3 and retinoic acid binding promote formation of a CRABP2 structure in which the retinoic acid binding pocket is occupied by an alternative lid conformation. Structural and functional analysis of CRABP2 and cyclin D3 mutants combined with AlphaFold models of the ternary CDK4/6-cyclin D3-CRABP2 complex supports the identification of an α-helical protein binding site on the cyclin D3 C-terminal cyclin box fold.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440035","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
PARG inhibition induces nuclear aggregation of PARylated PARP1 PARG 抑制可诱导 PARylated PARP1 的核聚集
IF 5.7 2区 生物学
Structure Pub Date : 2024-10-14 DOI: 10.1016/j.str.2024.09.006
Sateja Paradkar, Julia Purcell, Annie Cui, Sam Friedman, Katelyn J. Noronha, Matthew A. Murray, Ranjini K. Sundaram, Ranjit S. Bindra, Ryan B. Jensen
{"title":"PARG inhibition induces nuclear aggregation of PARylated PARP1","authors":"Sateja Paradkar, Julia Purcell, Annie Cui, Sam Friedman, Katelyn J. Noronha, Matthew A. Murray, Ranjini K. Sundaram, Ranjit S. Bindra, Ryan B. Jensen","doi":"10.1016/j.str.2024.09.006","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.006","url":null,"abstract":"Poly (ADP-ribose) glycohydrolase (PARG) inhibitors are currently under clinical development for the treatment of DNA repair-deficient cancers; however, their precise mechanism of action is still unclear. Here, we report that PARG inhibition leads to excessive PARylated poly (ADP-ribose) polymerase 1 (PARP1) reducing the ability of PARP1 to properly localize to sites of DNA damage. Strikingly, the mis-localized PARP1 accumulates as aggregates throughout the nucleus. Abrogation of the catalytic activity of PARP1 prevents aggregate formation, indicating that PAR chains play a key role in this process. Finally, we find that PARP1 nuclear aggregates were highly persistent and were associated with cleaved cytoplasmic PARP1, ultimately leading to cell death. Overall, our data uncover an unexpected mechanism of PARG inhibitor cytotoxicity, which will shed light on the use of these drugs as anti-cancer therapeutics.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431228","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 ligand promiscuity of the hydroxamate siderophore binding protein FtsB from Streptococcus pyogenes 化脓性链球菌中的羟基氨基甲酸酯苷元结合蛋白 FtsB 的配体杂合性的结构基础
IF 5.7 2区 生物学
Structure Pub Date : 2024-10-11 DOI: 10.1016/j.str.2024.09.018
Jorge Fernandez-Perez, Akinobu Senoo, Jose M.M. Caaveiro, Makoto Nakakido, Susana de Vega, Ichiro Nakagawa, Kouhei Tsumoto
{"title":"Structural basis for the ligand promiscuity of the hydroxamate siderophore binding protein FtsB from Streptococcus pyogenes","authors":"Jorge Fernandez-Perez, Akinobu Senoo, Jose M.M. Caaveiro, Makoto Nakakido, Susana de Vega, Ichiro Nakagawa, Kouhei Tsumoto","doi":"10.1016/j.str.2024.09.018","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.018","url":null,"abstract":"Pathogenic bacteria must secure the uptake of nutritional metals such as iron for their growth, making their import systems attractive targets for the development of new antimicrobial modalities. In the pathogenic bacterium <em>Streptococcus pyogenes,</em> the iron uptake system FtsABCD transports iron encapsulated by siderophores of the hydroxamate class. However, the inability of <em>S. pyogenes</em> to produce these metabolites makes the biological and clinical relevance of this route unresolved. Herein, we demonstrated that the periplasmic binding protein FtsB recognizes not only the hydroxamate siderophore ferrichrome, as previously documented, but also ferrioxamine E (FOE), ferrioxamine B (FOB), and bisucaberin (BIS), each of them with high affinity (nM level). Up to seven aromatic residues in the binding pocket accommodate the variable backbones of the different siderophores through CH-π interactions, explaining ligand promiscuity. Collectively, our observations revealed how <em>S. pyogenes</em> exploits the diverse xenosiderophores produced by other microorganisms as iron sources to secure this precious nutrient.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405131","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 dissection of the CMP-pseudaminic acid synthetase, PseF CMP 伪氨基酸合成酶 PseF 的结构剖析
IF 5.7 2区 生物学
Structure Pub Date : 2024-10-10 DOI: 10.1016/j.str.2024.09.017
Tessa Keenan, Andrew R. Cowan, Emily K.P. Flack, Natasha E. Hatton, Abigail J. Walklett, Gavin H. Thomas, Glyn R. Hemsworth, Martin A. Fascione
{"title":"Structural dissection of the CMP-pseudaminic acid synthetase, PseF","authors":"Tessa Keenan, Andrew R. Cowan, Emily K.P. Flack, Natasha E. Hatton, Abigail J. Walklett, Gavin H. Thomas, Glyn R. Hemsworth, Martin A. Fascione","doi":"10.1016/j.str.2024.09.017","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.017","url":null,"abstract":"Pseudaminic acid is a non-mammalian sugar found in the surface glycoconjugates of many bacteria, including several human pathogens, and is a virulence factor thought to facilitate immune evasion. The final step in the biosynthesis of the nucleotide activated form of the sugar, CMP-Pse5Ac7Ac is performed by a CMP-Pse5Ac7Ac synthetase (PseF). Here we present the biochemical and structural characterization of PseF from <em>Aeromonas caviae</em> (AcPseF), with AcPseF displaying metal-dependent activity over a broad pH and temperature range. Upon binding to CMP-Pse5Ac7Ac, AcPseF undergoes dynamic movements akin to other CMP-ulosonic acid synthetases. The enzyme clearly discriminates Pse5Ac7Ac from other ulosonic acids, through active site interactions with side-chain functional groups and by positioning the molecule in a hydrophobic pocket. Finally, we show that AcPseF binds the CMP-Pse5Ac7Ac side chain in the lowest energy conformation, a trend that we observed in the structures of other enzymes of this class.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398287","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
PROTAC-mediated activation, rather than degradation, of a nuclear receptor reveals complex ligand-receptor interaction network PROTAC 介导的核受体激活而非降解揭示了复杂的配体-受体相互作用网络
IF 5.7 2区 生物学
Structure Pub Date : 2024-10-09 DOI: 10.1016/j.str.2024.09.016
Andrew D. Huber, Wenwei Lin, Shyaron Poudel, Darcie J. Miller, Taosheng Chen
{"title":"PROTAC-mediated activation, rather than degradation, of a nuclear receptor reveals complex ligand-receptor interaction network","authors":"Andrew D. Huber, Wenwei Lin, Shyaron Poudel, Darcie J. Miller, Taosheng Chen","doi":"10.1016/j.str.2024.09.016","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.016","url":null,"abstract":"Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules containing a ligand for a protein of interest linked to an E3 ubiquitin ligase ligand that induce protein degradation through E3 recruitment to the target protein. Small changes in PROTAC linkers can have drastic consequences, including loss of degradation activity, but the structural mechanisms governing such changes are unclear. To study this phenomenon, we screened PROTACs of diverse targeting modalities and identified dTAG-13 as an activator of the xenobiotic-sensing pregnane X receptor (PXR), which promiscuously binds various ligands. Characterization of dTAG-13 analogs and precursors revealed interplay between the PXR-binding moiety, linker, and E3 ligand that altered PXR activity without inducing degradation. A crystal structure of PXR ligand binding domain bound to a precursor ligand showed ligand-induced binding pocket distortions and a linker-punctured tunnel to the protein exterior at a region incompatible with E3 complex formation, highlighting the effects of linker environment on PROTAC activity.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385777","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 of Clostridium perfringens enterotoxin bound to its human receptor, claudin-4 产气荚膜梭菌肠毒素与其人类受体 Claudin-4 结合的冷冻电子显微镜结构
IF 5.7 2区 生物学
Structure Pub Date : 2024-10-08 DOI: 10.1016/j.str.2024.09.015
Sewwandi S. Rathnayake, Satchal K. Erramilli, Anthony A. Kossiakoff, Alex J. Vecchio
{"title":"Cryo-EM structures of Clostridium perfringens enterotoxin bound to its human receptor, claudin-4","authors":"Sewwandi S. Rathnayake, Satchal K. Erramilli, Anthony A. Kossiakoff, Alex J. Vecchio","doi":"10.1016/j.str.2024.09.015","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.015","url":null,"abstract":"<em>Clostridium perfringens</em> enterotoxin (CpE) causes prevalent and deadly gastrointestinal disorders. CpE binds to receptors called claudins on the apical surfaces of small intestinal epithelium. Claudins normally regulate paracellular transport but are hijacked from doing so by CpE and are instead led to form claudin/CpE complexes. Claudin/CpE complexes are the building blocks of oligomeric β-barrel pores that penetrate the plasma membrane and induce gut cytotoxicity. Here, we present the structures of CpE in complex with its native claudin receptor in humans, claudin-4, using cryogenic electron microscopy. The structures reveal the architecture of the claudin/CpE complex, the residues used in binding, the orientation of CpE relative to the membrane, and CpE-induced changes to claudin-4. Further, structures and modeling allude to the biophysical procession from claudin/CpE complexes to cytotoxic β-barrel pores during pathogenesis. In full, this work proposes a model of claudin/CpE assembly and provides strategies to obstruct its formation to treat CpE diseases.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384294","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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