Pub Date : 2025-01-17DOI: 10.1016/j.str.2025.01.007
Erika Pellegrini, Pauline Juyoux, Jill von Velsen, Nicola J. Baxter, Hugh R.W. Dannatt, Yi Jin, Matthew J. Cliff, Jonathan P. Waltho, Matthew W. Bowler
(Structure 32, 1834–1846; October 3, 2024)
(结构32,1834-1846；2024年10月3日)
{"title":"Metal fluorides—multi-functional tools for the study of phosphoryl transfer enzymes, a practical guide","authors":"Erika Pellegrini, Pauline Juyoux, Jill von Velsen, Nicola J. Baxter, Hugh R.W. Dannatt, Yi Jin, Matthew J. Cliff, Jonathan P. Waltho, Matthew W. Bowler","doi":"10.1016/j.str.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.str.2025.01.007","url":null,"abstract":"(Structure <em>32</em>, 1834–1846; October 3, 2024)","PeriodicalId":22168,"journal":{"name":"Structure","volume":"18 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989515","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}
Pub Date : 2025-01-17DOI: 10.1016/j.str.2024.12.014
Sung-Hyun Hong, So Young An, Changkon Park, Youngim Kim, Eun-Hee Kim, Nak-Kyoon Kim, Jeong-Yong Suh
CRISPR-Cas is a bacterial defense system that employs RNA-guided endonucleases to destroy invading foreign nucleic acids. Bacteriophages produce anti-CRISPR (Acr) proteins to evade CRISPR-Cas defense during the infection. AcrIIC5, a type II-C Cas9 inhibitor, exhibits unusual variations in the local backbone fold between its orthologs. Here we investigated how the folding variations affect the inhibition of target Cas9 using AcrIIC5 orthologs. Structural comparison of free AcrIIC5Smu and AcrIIC5Nch confirmed that the folding variation correlated with characteristic indels in the helical region. Mutagenesis and biochemical assays combined with AlphaFold2 predictions identified key residues of AcrIIC5 orthologs important for Cas9 inhibition. Remarkably, AcrIIC5 orthologs employed divergent binding interfaces via folding variations to inhibit the Cas9 targets. Our study suggests that Acr proteins have evolved structural variants to diversify key interfaces for target Cas9, which could be beneficial for the adaptation of phages to evasive mutations on the Cas9 surface.
{"title":"Structural variants of AcrIIC5 inhibit Cas9 via divergent binding interfaces","authors":"Sung-Hyun Hong, So Young An, Changkon Park, Youngim Kim, Eun-Hee Kim, Nak-Kyoon Kim, Jeong-Yong Suh","doi":"10.1016/j.str.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.014","url":null,"abstract":"CRISPR-Cas is a bacterial defense system that employs RNA-guided endonucleases to destroy invading foreign nucleic acids. Bacteriophages produce anti-CRISPR (Acr) proteins to evade CRISPR-Cas defense during the infection. AcrIIC5, a type II-C Cas9 inhibitor, exhibits unusual variations in the local backbone fold between its orthologs. Here we investigated how the folding variations affect the inhibition of target Cas9 using AcrIIC5 orthologs. Structural comparison of free AcrIIC5<sub>Smu</sub> and AcrIIC5<sub>Nch</sub> confirmed that the folding variation correlated with characteristic indels in the helical region. Mutagenesis and biochemical assays combined with AlphaFold2 predictions identified key residues of AcrIIC5 orthologs important for Cas9 inhibition. Remarkably, AcrIIC5 orthologs employed divergent binding interfaces via folding variations to inhibit the Cas9 targets. Our study suggests that Acr proteins have evolved structural variants to diversify key interfaces for target Cas9, which could be beneficial for the adaptation of phages to evasive mutations on the Cas9 surface.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"4 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987467","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}
Pub Date : 2025-01-15DOI: 10.1016/j.str.2024.12.013
Sebastian Kenny, Shalini Iyer, Clinton A. Gabel, Natalia Tegenfeldt, Andrew G. DeMarco, Mark C. Hall, Leifu Chang, V. Jo Davisson, Scott Vande Pol, Chittaranjan Das
High-risk human papillomavirus E6 oncoprotein is a model system for the recognition and degradation of cellular p53 tumor suppressor protein. There remains a gap in the understanding of the ubiquitin transfer reaction, including placement of the E6AP catalytic HECT domain of the ligase concerning the p53 substrate and how E6 itself is protected from ubiquitination. We determined the cryoelectron microscopy (cryo-EM) structure of the E6AP/E6/p53 complex, related the structure to in vivo modeling of the tri-molecular complex, and identified structural interactions associated with activation of the ubiquitin ligase function. The structure reveals that the N-terminal ordered domain (NOD) in E6AP has a terminal alpha helix that mediates the interaction of the NOD with the HECT domain of E6AP and protects the HPV-E6 protein from ubiquitination. In addition, this NOD helix is required for E6AP ligase function by contributing to the affinity of the E6-E6AP association, modulating E6 substrate recognition, while displacing UbcH7.
{"title":"Structure of E6AP in complex with HPV16-E6 and p53 reveals a novel ordered domain important for E3 ligase activation","authors":"Sebastian Kenny, Shalini Iyer, Clinton A. Gabel, Natalia Tegenfeldt, Andrew G. DeMarco, Mark C. Hall, Leifu Chang, V. Jo Davisson, Scott Vande Pol, Chittaranjan Das","doi":"10.1016/j.str.2024.12.013","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.013","url":null,"abstract":"High-risk human papillomavirus E6 oncoprotein is a model system for the recognition and degradation of cellular p53 tumor suppressor protein. There remains a gap in the understanding of the ubiquitin transfer reaction, including placement of the E6AP catalytic HECT domain of the ligase concerning the p53 substrate and how E6 itself is protected from ubiquitination. We determined the cryoelectron microscopy (cryo-EM) structure of the E6AP/E6/p53 complex, related the structure to <em>in vivo</em> modeling of the tri-molecular complex, and identified structural interactions associated with activation of the ubiquitin ligase function. The structure reveals that the N-terminal ordered domain (NOD) in E6AP has a terminal alpha helix that mediates the interaction of the NOD with the HECT domain of E6AP and protects the HPV-E6 protein from ubiquitination. In addition, this NOD helix is required for E6AP ligase function by contributing to the affinity of the E6-E6AP association, modulating E6 substrate recognition, while displacing UbcH7.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"41 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981362","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}
Pub Date : 2025-01-13DOI: 10.1016/j.str.2024.12.012
Benjamin Russell Lewis, Muhammad R. Uddin, Katie M. Kuo, Laila M.N. Shah, Nicola J. Harris, Paula J. Booth, Dietmar Hammerschmid, James C. Gumbart, Helen I. Zgurskaya, Eamonn Reading
Tripartite resistance nodulation and cell division multidrug efflux pumps span the periplasm and are major drivers of multidrug resistance among gram-negative bacteria. Cations, such as Mg2+, become concentrated within the periplasm and, in contrast to the cytoplasm, its pH is sensitive to conditions outside the cell. Here, we reveal an interplay between Mg2+ and pH in modulating the structural dynamics of the periplasmic adapter protein, AcrA, and its function within the prototypical AcrAB-TolC multidrug pump from Escherichia coli. In the absence of Mg2+, AcrA becomes increasingly plastic within acidic conditions, but when Mg2+ is bound this is ameliorated, resulting instead in domain specific organization. We establish a unique histidine residue directs these dynamics and is essential for sustaining pump activity across acidic, neutral, and basic regimes. Overall, we propose Mg2+ conserves AcrA structural mobility to ensure optimal AcrAB-TolC function within rapidly changing environments commonly faced during bacterial infection and colonization.
{"title":"Mg2+-dependent mechanism of environmental versatility in a multidrug efflux pump","authors":"Benjamin Russell Lewis, Muhammad R. Uddin, Katie M. Kuo, Laila M.N. Shah, Nicola J. Harris, Paula J. Booth, Dietmar Hammerschmid, James C. Gumbart, Helen I. Zgurskaya, Eamonn Reading","doi":"10.1016/j.str.2024.12.012","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.012","url":null,"abstract":"Tripartite resistance nodulation and cell division multidrug efflux pumps span the periplasm and are major drivers of multidrug resistance among gram-negative bacteria. Cations, such as Mg<sup>2+</sup>, become concentrated within the periplasm and, in contrast to the cytoplasm, its pH is sensitive to conditions outside the cell. Here, we reveal an interplay between Mg<sup>2+</sup> and pH in modulating the structural dynamics of the periplasmic adapter protein, AcrA, and its function within the prototypical AcrAB-TolC multidrug pump from <em>Escherichia coli</em>. In the absence of Mg<sup>2+</sup>, AcrA becomes increasingly plastic within acidic conditions, but when Mg<sup>2+</sup> is bound this is ameliorated, resulting instead in domain specific organization. We establish a unique histidine residue directs these dynamics and is essential for sustaining pump activity across acidic, neutral, and basic regimes. Overall, we propose Mg<sup>2+</sup> conserves AcrA structural mobility to ensure optimal AcrAB-TolC function within rapidly changing environments commonly faced during bacterial infection and colonization.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"39 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967995","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}
Pub Date : 2025-01-13DOI: 10.1016/j.str.2024.12.011
Elżbieta Wątor-Wilk, Piotr Wilk, Przemysław Grudnik
Deoxyhypusination is the first rate-limiting step of the unique post-translational modification—hypusination—that is catalyzed by deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). This modification is essential for the activation of translation factor 5A in eukaryotes (eIF5A) and Archaea (aIF5A). This perspective focuses on the structural biology of deoxyhypusination complexes in eukaryotic and archaeal organisms. Based on recently published crystal and cryogenic electron microscopy (cryo-EM) structures of deoxyhypusination complexes from three different organisms, we compare the structural features and stoichiometries of DHS-IF5A complexes across different species. We discuss conserved elements in the active site architecture and binding interfaces as well as significant differences in their stoichiometry and regulation mechanisms. The structural insights provide a comprehensive understanding of the deoxyhypusination process and highlight evolutionary adaptations across the domains of life. Future research should focus on the regulatory mechanisms governing DHS activity and the functional implications of stoichiometric variations in different organisms.
{"title":"The structural biology of deoxyhypusination complexes","authors":"Elżbieta Wątor-Wilk, Piotr Wilk, Przemysław Grudnik","doi":"10.1016/j.str.2024.12.011","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.011","url":null,"abstract":"Deoxyhypusination is the first rate-limiting step of the unique post-translational modification—hypusination—that is catalyzed by deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). This modification is essential for the activation of translation factor 5A in eukaryotes (eIF5A) and Archaea (aIF5A). This perspective focuses on the structural biology of deoxyhypusination complexes in eukaryotic and archaeal organisms. Based on recently published crystal and cryogenic electron microscopy (cryo-EM) structures of deoxyhypusination complexes from three different organisms, we compare the structural features and stoichiometries of DHS-IF5A complexes across different species. We discuss conserved elements in the active site architecture and binding interfaces as well as significant differences in their stoichiometry and regulation mechanisms. The structural insights provide a comprehensive understanding of the deoxyhypusination process and highlight evolutionary adaptations across the domains of life. Future research should focus on the regulatory mechanisms governing DHS activity and the functional implications of stoichiometric variations in different organisms.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"84 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967974","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}
Pub Date : 2025-01-10DOI: 10.1016/j.str.2024.12.010
Michael DiDonato, Carolina Turk Simpson, Todd Vo, Mark Knuth, Bernhard Geierstanger, Joanna Jamontt, David H. Jones, John W. Fathman, Donnie DeLarosa, Tobias Junt, Damien Picard, Ulrike Sommer, Morten Bagger, Eric Peters, Shelly Meeusen, Glen Spraggon
Inflammatory bowel disease (IBD) consists of chronic conditions that severely impact a patient’s health and quality of life. Interleukin-10 (IL-10), a potent anti-inflammatory cytokine has strong genetic links to IBD susceptibility and has shown strong efficacy in IBD rodent models, suggesting it has great therapeutic potential. However, when tested in clinical trials for IBD, recombinant human IL-10 (rhIL-10) showed weak and inconsistent efficacy due to its short half-life and pro-inflammatory properties that counteract the anti-inflammatory efficacy. Here we present an engineered, IL-10, antibody-graft therapeutic (GFT-IL10M) designed to rectify these issues. GFT-IL10M combines the half-life extension properties of a monoclonal IgG antibody with altered IL-10 cell-type selective signaling, retaining desirable signaling on monocytes while reducing unwanted signaling on T, natural killer (NK), and B cells. Our structural and biochemical results indicate that the altered IL-10 topology in GFT-IL10M leads to a predominantly anti-inflammatory profile, potentially altering cell-type specific signaling patterns and extending half-life.
{"title":"A novel interleukin-10 antibody graft to treat inflammatory bowel disease","authors":"Michael DiDonato, Carolina Turk Simpson, Todd Vo, Mark Knuth, Bernhard Geierstanger, Joanna Jamontt, David H. Jones, John W. Fathman, Donnie DeLarosa, Tobias Junt, Damien Picard, Ulrike Sommer, Morten Bagger, Eric Peters, Shelly Meeusen, Glen Spraggon","doi":"10.1016/j.str.2024.12.010","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.010","url":null,"abstract":"Inflammatory bowel disease (IBD) consists of chronic conditions that severely impact a patient’s health and quality of life. Interleukin-10 (IL-10), a potent anti-inflammatory cytokine has strong genetic links to IBD susceptibility and has shown strong efficacy in IBD rodent models, suggesting it has great therapeutic potential. However, when tested in clinical trials for IBD, recombinant human IL-10 (rhIL-10) showed weak and inconsistent efficacy due to its short half-life and pro-inflammatory properties that counteract the anti-inflammatory efficacy. Here we present an engineered, IL-10, antibody-graft therapeutic (GFT-IL10M) designed to rectify these issues. GFT-IL10M combines the half-life extension properties of a monoclonal IgG antibody with altered IL-10 cell-type selective signaling, retaining desirable signaling on monocytes while reducing unwanted signaling on T, natural killer (NK), and B cells. Our structural and biochemical results indicate that the altered IL-10 topology in GFT-IL10M leads to a predominantly anti-inflammatory profile, potentially altering cell-type specific signaling patterns and extending half-life.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"1 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939573","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}
Pub Date : 2025-01-10DOI: 10.1016/j.str.2024.12.008
Sarah R. Stevenson, Svetomir B. Tzokov, Indrajit Lahiri, Kathryn R. Ayscough, Per A. Bullough
The core component of the actin cytoskeleton is the globular protein G-actin, which reversibly polymerizes into filaments (F-actin). Budding yeast possesses a single actin that shares 87%–89% sequence identity with vertebrate actin isoforms. Previous structural studies indicate very close overlap of main-chain backbones. Intriguingly, however, substitution of yeast ACT1 with vertebrate β-cytoplasmic actin severely disrupts cell function and the substitution with a skeletal muscle isoform is lethal. Here we report a 2.5 Å structure of budding yeast F-actin. Previously unresolved side-chain information allows us to highlight four main differences in the comparison of yeast and vertebrate ADP F-actins: a more open nucleotide binding pocket; a more solvent exposed C-terminus; a rearrangement of inter-subunit binding interactions in the vicinity of the D loop and changes in the hydrogen bonding network in the vicinity of histidine 73 (yeast actin) and methyl-histidine 73 (vertebrate actin).
肌动蛋白细胞骨架的核心成分是球形蛋白g -肌动蛋白，它可逆地聚合成细丝（f -肌动蛋白）。出芽酵母具有一个单一的肌动蛋白，与脊椎动物肌动蛋白同工型具有87%-89%的序列一致性。先前的结构研究表明，主链主干的重叠非常紧密。然而，有趣的是，用脊椎动物β-细胞质肌动蛋白替代酵母ACT1严重破坏细胞功能，并用骨骼肌同种异构体替代是致命的。在这里，我们报告了出芽酵母f -肌动蛋白的2.5 Å结构。先前未解决的侧链信息使我们能够突出酵母和脊椎动物ADP f -actin比较中的四个主要差异：更开放的核苷酸结合袋；一个更具溶剂性的暴露c端；D环附近亚基间结合相互作用的重排以及组氨酸73（酵母肌动蛋白）和甲基组氨酸73（脊椎动物肌动蛋白）附近氢键网络的变化。
{"title":"Cryo-EM reconstruction of yeast ADP-actin filament at 2.5 Å resolution. A comparison with vertebrate F-actin","authors":"Sarah R. Stevenson, Svetomir B. Tzokov, Indrajit Lahiri, Kathryn R. Ayscough, Per A. Bullough","doi":"10.1016/j.str.2024.12.008","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.008","url":null,"abstract":"The core component of the actin cytoskeleton is the globular protein G-actin, which reversibly polymerizes into filaments (F-actin). Budding yeast possesses a single actin that shares 87%–89% sequence identity with vertebrate actin isoforms. Previous structural studies indicate very close overlap of main-chain backbones. Intriguingly, however, substitution of yeast <em>ACT1</em> with vertebrate β-cytoplasmic actin severely disrupts cell function and the substitution with a skeletal muscle isoform is lethal. Here we report a 2.5 Å structure of budding yeast F-actin. Previously unresolved side-chain information allows us to highlight four main differences in the comparison of yeast and vertebrate ADP F-actins: a more open nucleotide binding pocket; a more solvent exposed C-terminus; a rearrangement of inter-subunit binding interactions in the vicinity of the D loop and changes in the hydrogen bonding network in the vicinity of histidine 73 (yeast actin) and methyl-histidine 73 (vertebrate actin).","PeriodicalId":22168,"journal":{"name":"Structure","volume":"8 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939576","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}
Pub Date : 2025-01-10DOI: 10.1016/j.str.2024.12.009
Zhenlin Ouyang, Wenbo He, Di Wu, Hao An, Lei Duan, Min Jiao, Xiaoyu He, Qinyue Yu, Jiaxin Zhang, Qian Qin, Ruochen Wang, Fang Zheng, Peter M. Hwang, Xiaoting Hua, Li Zhu, Yurong Wen
Multidrug-resistant Acinetobacter baumannii has emerged as one of the most antibiotic-resistant bacterial pathogens associated with nosocomial infection, with its resistance highly depending on multiple multidrug efflux pumps. Here, we report the cryoelectron microscopy (cryo-EM) structure of Acinetobacter drug efflux G (AdeG), the inner membrane component of one of three important resistance-nodulation-cell division (RND) pump family members in A. baumannii, which is involved in drug resistance to chloramphenicol, trimethoprim, ciprofloxacin, and clindamycin. We systematically compare the structures and substrate binding specificities of AdeG, AdeB, and AdeJ multidrug efflux pumps via molecular docking, revealing potential determinants for drug binding. Knockout experiments demonstrate a functional complementarity between AdeABC, AdeFGH, and AdeIJK. Our study provides a structural understanding of A. baumannii multidrug efflux pump AdeG and reveals complementary drug efflux activity between AdeG and other RND efflux pumps, which may promote further rational drug discovery efforts targeting multidrug efflux pumps.
{"title":"Cryo-EM structure and complementary drug efflux activity of the Acinetobacter baumannii multidrug efflux pump AdeG","authors":"Zhenlin Ouyang, Wenbo He, Di Wu, Hao An, Lei Duan, Min Jiao, Xiaoyu He, Qinyue Yu, Jiaxin Zhang, Qian Qin, Ruochen Wang, Fang Zheng, Peter M. Hwang, Xiaoting Hua, Li Zhu, Yurong Wen","doi":"10.1016/j.str.2024.12.009","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.009","url":null,"abstract":"Multidrug-resistant <em>Acinetobacter baumannii</em> has emerged as one of the most antibiotic-resistant bacterial pathogens associated with nosocomial infection, with its resistance highly depending on multiple multidrug efflux pumps. Here, we report the cryoelectron microscopy (cryo-EM) structure of <em>Acinetobacter</em> drug efflux G (AdeG), the inner membrane component of one of three important resistance-nodulation-cell division (RND) pump family members in <em>A. baumannii</em>, which is involved in drug resistance to chloramphenicol, trimethoprim, ciprofloxacin, and clindamycin. We systematically compare the structures and substrate binding specificities of AdeG, AdeB, and AdeJ multidrug efflux pumps via molecular docking, revealing potential determinants for drug binding. Knockout experiments demonstrate a functional complementarity between AdeABC, AdeFGH, and AdeIJK. Our study provides a structural understanding of <em>A. baumannii</em> multidrug efflux pump AdeG and reveals complementary drug efflux activity between AdeG and other RND efflux pumps, which may promote further rational drug discovery efforts targeting multidrug efflux pumps.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"31 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939572","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}
Pub Date : 2025-01-02DOI: 10.1016/j.str.2024.12.003
Hannah Ochner, Tanmay A.M. Bharat
In a recent issue of Nature Methods, Pfeil-Gardiner et al. (2024)1 combine electron energy-loss spectroscopy and single-particle cryoelectron microscopy to allow the spatially resolved imaging of the elemental composition of macromolecules.
{"title":"Cryoelectron microscopy with elemental sensitivity","authors":"Hannah Ochner, Tanmay A.M. Bharat","doi":"10.1016/j.str.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.003","url":null,"abstract":"In a recent issue of <em>Nature Methods</em>, Pfeil-Gardiner et al. (2024)<span><span><sup>1</sup></span></span> combine electron energy-loss spectroscopy and single-particle cryoelectron microscopy to allow the spatially resolved imaging of the elemental composition of macromolecules.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"92 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912107","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}
Pub Date : 2025-01-02DOI: 10.1016/j.str.2024.11.012
Janosch Hennig, Cristina Paulino
The data presented at the 9th International Murnau Conference on September 18–21, 2024, the largest recurring structural biology meeting in Central Europe, illustrated the thriving state of the structural biology community. This is largely attributed to the ground-breaking developments over the last decade, which were intensely discussed during the meeting.
{"title":"4D structural biology—The 9th Murnau Conference on structural biology","authors":"Janosch Hennig, Cristina Paulino","doi":"10.1016/j.str.2024.11.012","DOIUrl":"https://doi.org/10.1016/j.str.2024.11.012","url":null,"abstract":"The data presented at the 9<sup>th</sup> International Murnau Conference on September 18–21, 2024, the largest recurring structural biology meeting in Central Europe, illustrated the thriving state of the structural biology community. This is largely attributed to the ground-breaking developments over the last decade, which were intensely discussed during the meeting.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"34 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912017","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：