Nature chemical biology最新文献_第10页

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-06-19 DOI: 10.1038/s41589-024-01643-z

Mollie I. Sweeney, David M. Tobin

引用次数: 0

3-Hydroxykynurenine targets kainate receptors to promote defense against infection 3-羟基犬尿氨酸靶向凯恩酸受体，促进对感染的防御

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-06-19 DOI: 10.1038/s41589-024-01635-z

Margarita Parada-Kusz, Anne E. Clatworthy, Emily R. Goering, Stephanie M. Blackwood, Jack Y. Shigeta, Eivgeni Mashin, Elizabeth J. Salm, Catherine Choi, Senya Combs, Jenny S. W. Lee, Carlos Rodriguez-Osorio, Clary Clish, Susumu Tomita, Deborah T. Hung

{"title":"3-Hydroxykynurenine targets kainate receptors to promote defense against infection","authors":"Margarita Parada-Kusz, Anne E. Clatworthy, Emily R. Goering, Stephanie M. Blackwood, Jack Y. Shigeta, Eivgeni Mashin, Elizabeth J. Salm, Catherine Choi, Senya Combs, Jenny S. W. Lee, Carlos Rodriguez-Osorio, Clary Clish, Susumu Tomita, Deborah T. Hung","doi":"10.1038/s41589-024-01635-z","DOIUrl":"https://doi.org/10.1038/s41589-024-01635-z","url":null,"abstract":"Bacterial infection involves a complex interaction between the pathogen and host where the outcome of infection is not solely determined by pathogen eradication. To identify small molecules that promote host survival by altering the host–pathogen dynamic, we conducted an in vivo chemical screen using zebrafish embryos and found that treatment with 3-hydroxykynurenine (3-HK) protects from lethal bacterial infection. 3-HK, a metabolite produced through host tryptophan metabolism, has no direct antibacterial activity but enhances host survival by restricting bacterial expansion in macrophages through a systemic mechanism that targets kainate-sensitive glutamate receptors. These findings reveal a new pathway by which tryptophan metabolism and kainate-sensitive glutamate receptors function and interact to modulate immunity, with important implications for the coordination between the immune and nervous systems in pathological conditions.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Quantitative control of subcellular protein localization with a photochromic dimerizer 用光变色二聚体定量控制亚细胞蛋白质定位

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-06-18 DOI: 10.1038/s41589-024-01654-w

Takato Mashita, Toshiyuki Kowada, Hayashi Yamamoto, Satoshi Hamaguchi, Toshizo Sato, Toshitaka Matsui, Shin Mizukami

{"title":"Quantitative control of subcellular protein localization with a photochromic dimerizer","authors":"Takato Mashita, Toshiyuki Kowada, Hayashi Yamamoto, Satoshi Hamaguchi, Toshizo Sato, Toshitaka Matsui, Shin Mizukami","doi":"10.1038/s41589-024-01654-w","DOIUrl":"https://doi.org/10.1038/s41589-024-01654-w","url":null,"abstract":"Artificial control of intracellular protein dynamics with high precision provides deep insight into complicated biomolecular networks. Optogenetics and caged compound-based chemically induced dimerization (CID) systems are emerging as tools for spatiotemporally regulating intracellular protein dynamics. However, both technologies face several challenges for accurate control such as the duration of activation, deactivation rate and repetition cycles. Herein, we report a photochromic CID system that uses the photoisomerization of a ligand so that both association and dissociation are controlled by light, enabling quick, repetitive and quantitative regulation of the target protein localization upon illumination with violet and green light. We also demonstrate the usability of the photochromic CID system as a potential tool to finely manipulate intracellular protein dynamics during multicolor fluorescence imaging to study diverse cellular processes. We use this system to manipulate PTEN-induced kinase 1 (PINK1)–Parkin-mediated mitophagy, showing that PINK1 recruitment to the mitochondria can promote Parkin recruitment to proceed with mitophagy.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Architecture of the RNF1 complex that drives biological nitrogen fixation 驱动生物固氮的 RNF1 复合物的结构

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-06-18 DOI: 10.1038/s41589-024-01641-1

Lin Zhang, Oliver Einsle

{"title":"Architecture of the RNF1 complex that drives biological nitrogen fixation","authors":"Lin Zhang, Oliver Einsle","doi":"10.1038/s41589-024-01641-1","DOIUrl":"10.1038/s41589-024-01641-1","url":null,"abstract":"Biological nitrogen fixation requires substantial metabolic energy in form of ATP as well as low-potential electrons that must derive from central metabolism. During aerobic growth, the free-living soil diazotroph Azotobacter vinelandii transfers electrons from the key metabolite NADH to the low-potential ferredoxin FdxA that serves as a direct electron donor to the dinitrogenase reductases. This process is mediated by the RNF complex that exploits the proton motive force over the cytoplasmic membrane to lower the midpoint potential of the transferred electron. Here we report the cryogenic electron microscopy structure of the nitrogenase-associated RNF complex of A. vinelandii, a seven-subunit membrane protein assembly that contains four flavin cofactors and six iron–sulfur centers. Its function requires the strict coupling of electron and proton transfer but also involves major conformational changes within the assembly that can be traced with a combination of electron microscopy and modeling. Biological nitrogen fixation requires low-potential electrons from ferredoxin or flavodoxin. Here the authors show how the soil diazotroph Azotobacter vinelandii employs the NADH:ferredoxin oxidoreductase RNF1 complex to lower the midpoint potential of the electron from NADH to reduce ferredoxin.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The realization of CRISPR gene therapy 实现 CRISPR 基因疗法

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-06-13 DOI: 10.1038/s41589-024-01645-x

Yitong Ma, Lei S. Qi

引用次数: 0

Optimizing multicopy chromosomal integration for stable high-performing strains 优化多拷贝染色体整合，培育稳定的高效菌株

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-06-10 DOI: 10.1038/s41589-024-01650-0

Fei Du, Zijia Li, Xin Li, Duoduo Zhang, Feng Zhang, Zixu Zhang, Yingshuang Xu, Jin Tang, Yongqian Li, Xingxu Huang, Yang Gu, Xiaoman Sun, He Huang

{"title":"Optimizing multicopy chromosomal integration for stable high-performing strains","authors":"Fei Du, Zijia Li, Xin Li, Duoduo Zhang, Feng Zhang, Zixu Zhang, Yingshuang Xu, Jin Tang, Yongqian Li, Xingxu Huang, Yang Gu, Xiaoman Sun, He Huang","doi":"10.1038/s41589-024-01650-0","DOIUrl":"https://doi.org/10.1038/s41589-024-01650-0","url":null,"abstract":"The copy number of genes in chromosomes can be modified by chromosomal integration to construct efficient microbial cell factories but the resulting genetic systems are prone to failure or instability from triggering homologous recombination in repetitive DNA sequences. Finding the optimal copy number of each gene in a pathway is also time and labor intensive. To overcome these challenges, we applied a multiple nonrepetitive coding sequence calculator that generates sets of coding DNA sequence (CDS) variants. A machine learning method was developed to calculate the optimal copy number combination of genes in a pathway. We obtained an engineered Yarrowia lipolytica strain for eicosapentaenoic acid biosynthesis in 6 months, producing the highest titer of 27.5 g l−1 in a 50-liter bioreactor. Moreover, the lycopene production in Escherichia coli was also greatly improved. Importantly, all engineered strains of Y. lipolytica, E. coli and Saccharomyces cerevisiae constructed with nonrepetitive CDSs maintained genetic stability.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 de novo designed coiled coil-based switch regulates the microtubule motor kinesin-1 全新设计的基于线圈的开关调控微管马达驱动蛋白-1

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-06-07 DOI: 10.1038/s41589-024-01640-2

Jessica A. Cross, William M. Dawson, Shivam R. Shukla, Johannes F. Weijman, Judith Mantell, Mark P. Dodding, Derek N. Woolfson

{"title":"A de novo designed coiled coil-based switch regulates the microtubule motor kinesin-1","authors":"Jessica A. Cross, William M. Dawson, Shivam R. Shukla, Johannes F. Weijman, Judith Mantell, Mark P. Dodding, Derek N. Woolfson","doi":"10.1038/s41589-024-01640-2","DOIUrl":"10.1038/s41589-024-01640-2","url":null,"abstract":"Many enzymes are allosterically regulated via conformational change; however, our ability to manipulate these structural changes and control function is limited. Here we install a conformational switch for allosteric activation into the kinesin-1 microtubule motor in vitro and in cells. Kinesin-1 is a heterotetramer that accesses open active and closed autoinhibited states. The equilibrium between these states centers on a flexible elbow within a complex coiled-coil architecture. We target the elbow to engineer a closed state that can be opened with a de novo designed peptide. The alternative states are modeled computationally and confirmed by biophysical measurements and electron microscopy. In cells, peptide-driven activation increases kinesin transport, demonstrating a primary role for conformational switching in regulating motor activity. The designs are enabled by our understanding of ubiquitous coiled-coil structures, opening possibilities for controlling other protein activities. The kinesin-1 motor protein accesses open active and closed autoinhibited states. These states are regulated by a flexible elbow within a complex coiled-coil architecture. Now, a conformational switch has been developed by engineering the elbow to create a closed state that can be controllably opened with a de novo designed peptide to increase kinesin transport inside cells.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41589-024-01640-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

High-resolution structure of a novel fluorogenic RNA aptamer 新型荧光 RNA 合体的高分辨率结构

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-06-06 DOI: 10.1038/s41589-024-01652-y

引用次数: 0

Mechanisms of neutralization of toxSAS from toxin–antitoxin modules 毒素-抗毒素模块中和 toxSAS 的机制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-06-04 DOI: 10.1038/s41589-024-01630-4

Lucia Dominguez-Molina, Tatsuaki Kurata, Albinas Cepauskas, Dannele Echemendia-Blanco, Safia Zedek, Ariel Talavera-Perez, Gemma C. Atkinson, Vasili Hauryliuk, Abel Garcia-Pino

{"title":"Mechanisms of neutralization of toxSAS from toxin–antitoxin modules","authors":"Lucia Dominguez-Molina, Tatsuaki Kurata, Albinas Cepauskas, Dannele Echemendia-Blanco, Safia Zedek, Ariel Talavera-Perez, Gemma C. Atkinson, Vasili Hauryliuk, Abel Garcia-Pino","doi":"10.1038/s41589-024-01630-4","DOIUrl":"https://doi.org/10.1038/s41589-024-01630-4","url":null,"abstract":"Toxic small alarmone synthetase (toxSAS) enzymes constitute a family of bacterial effectors present in toxin–antitoxin and secretion systems. toxSASs act through either translation inhibition mediated by pyrophosphorylation of transfer RNA (tRNA) CCA ends or synthesis of the toxic alarmone adenosine pentaphosphate ((pp)pApp) and adenosine triphosphate (ATP) depletion, exemplified by FaRel2 and FaRel, respectively. However, structural bases of toxSAS neutralization are missing. Here we show that the pseudo-Zn2+ finger domain (pZFD) of the ATfaRel2 antitoxin precludes access of ATP to the pyrophosphate donor site of the FaRel2 toxin, without affecting recruitment of the tRNA pyrophosphate acceptor. By contrast, (pp)pApp-producing toxSASs are inhibited by Tis1 antitoxin domains though occlusion of the pyrophosphate acceptor-binding site. Consequently, the auxiliary pZFD of AT2faRel is dispensable for FaRel neutralization. Collectively, our study establishes the general principles of toxSAS inhibition by structured antitoxin domains, with the control strategy directly coupled to toxSAS substrate specificity.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Enediyne natural product biosynthesis unified by a diiodotetrayne intermediate 由二碘四炔中间体统一的烯二炔天然产物生物合成

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-06-03 DOI: 10.1038/s41589-024-01636-y

Chun Gui, Edward Kalkreuter, Lukas Lauterbach, Dong Yang, Ben Shen

{"title":"Enediyne natural product biosynthesis unified by a diiodotetrayne intermediate","authors":"Chun Gui, Edward Kalkreuter, Lukas Lauterbach, Dong Yang, Ben Shen","doi":"10.1038/s41589-024-01636-y","DOIUrl":"10.1038/s41589-024-01636-y","url":null,"abstract":"Enediyne natural products are renowned for their potent cytotoxicities but the biosynthesis of their defining 1,5-diyne-3-ene core moiety remains largely enigmatic. Since the discovery of the enediyne polyketide synthase cassette in 2002, genome sequencing has revealed thousands of distinct enediyne biosynthetic gene clusters, each harboring the conserved enediyne polyketide synthase cassette. Here we report that (1) the products of this cassette are an iodoheptaene, a diiodotetrayne and two pentaynes; (2) the diiodotetrayne represents a common biosynthetic intermediate for all known enediynes; and (3) cryptic iodination can be exploited to increase enediyne titers. These findings establish a unified biosynthetic pathway for the enediynes, set the stage to further advance enediyne core biosynthesis and enable fundamental breakthroughs in chemistry, enzymology and translational applications of enediyne natural products. Enediyne natural products are potent antitumor antibiotics but the biosynthesis of their 1,5-diyne-3-ene core has remained enigmatic for decades. Here a diiodotetrayne is reported as a universal enediyne biosynthetic intermediate of this core, obtained upon cryptic iodination.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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