Nature chemical biology最新文献

Nuclear ubiquitination permits Hippo–YAP signal for liver development and tumorigenesis 核泛素化允许Hippo-YAP信号参与肝脏发育和肿瘤发生

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-16 DOI: 10.1038/s41589-025-01901-8

Jinsong Wei, Zhifa Cao, Qing Li, Xiaoyu Li, Qingzhe Wang, Yiming Zhang, Run Zhang, Xingru Wu, Quanhui Dai, Xinyang Li, Zhaocai Zhou, Fenyong Sun, Shi Jiao, Bing Zhao

{"title":"Nuclear ubiquitination permits Hippo–YAP signal for liver development and tumorigenesis","authors":"Jinsong Wei, Zhifa Cao, Qing Li, Xiaoyu Li, Qingzhe Wang, Yiming Zhang, Run Zhang, Xingru Wu, Quanhui Dai, Xinyang Li, Zhaocai Zhou, Fenyong Sun, Shi Jiao, Bing Zhao","doi":"10.1038/s41589-025-01901-8","DOIUrl":"https://doi.org/10.1038/s41589-025-01901-8","url":null,"abstract":"Hippo–YAP signaling is crucial to organ development and tumorigenesis. VGLL4, which occupies TEAD to prevent YAP binding, is the main transcriptional repressor of Hippo–YAP activity. Here we identified the nuclear E3 ligase ubiquitin protein ligase E3 component n-recognin 5 (UBR5) poly-ubiquitinated VGLL4 at Lys61 for its degradation, which permits Hippo–YAP signaling for the development of the liver biliary system in mice and multiple cancers in humans. In mouse liver development, Ubr5 and Vgll4 exhibited reciprocal expression patterns spatiotemporally. Ubr5 deletion impaired cholangiocyte development and hepatocyte reprogramming, which could be efficiently rescued by restoring Hippo–YAP through ablating Vgll4. We also found that the UBR5–VGLL4–YAP axis is associated with the progression of human pan-cancers. Targeting nuclear E3 ligases in multiple types of patient-derived tumor organoids suppressed their expansion. Our identification of UBR5 as the bona fide E3 ligase of VGLL4 offers a molecular framework of nuclear Hippo–YAP regulation and suggests nuclear ubiquitination as a potential therapeutic target for YAP-dependent malignancies.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"5 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066296","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

Direct nitrogen–nitrogen bond formation by an enzyme from the negamycin biosynthetic pathway 由一种酶从负霉素生物合成途径直接形成氮-氮键

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-15 DOI: 10.1038/s41589-025-01899-z

引用次数: 0

Development of an allosteric adhesion GPCR nanobody with therapeutic potential 具有治疗潜力的变构黏附GPCR纳米体的研制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-15 DOI: 10.1038/s41589-025-01896-2

Yuan Zheng, Dan Jiang, Yan Lu, Chao Zhang, Shen-Ming Huang, Haocheng Lin, Daolai Zhang, Shengchao Guo, Jifei Han, Jun Chen, Yaxuan He, Mingxiang Zhang, Yanhui Gao, Yongyuan Guo, Ran Wei, Ming Xia, Yingying Qin, Zhaoqian Liu, Fan Yang, Shaohua Ge, Fan Yi, Xiao Yu, Hui Lin, Peng Xiao, Jin-Peng Sun, Shiqing Feng

{"title":"Development of an allosteric adhesion GPCR nanobody with therapeutic potential","authors":"Yuan Zheng, Dan Jiang, Yan Lu, Chao Zhang, Shen-Ming Huang, Haocheng Lin, Daolai Zhang, Shengchao Guo, Jifei Han, Jun Chen, Yaxuan He, Mingxiang Zhang, Yanhui Gao, Yongyuan Guo, Ran Wei, Ming Xia, Yingying Qin, Zhaoqian Liu, Fan Yang, Shaohua Ge, Fan Yi, Xiao Yu, Hui Lin, Peng Xiao, Jin-Peng Sun, Shiqing Feng","doi":"10.1038/s41589-025-01896-2","DOIUrl":"https://doi.org/10.1038/s41589-025-01896-2","url":null,"abstract":"Allosteric modulation of receptor responses to endogenous agonists has therapeutic value, maintaining ligand profiles, reducing side effects and restoring mutant responses. Adhesion G-protein-coupled receptors (aGPCRs), with large N termini, are ideal for allosteric modulator development. We designed a nanobody strategy targeting ADGRG2 N-terminal fragments and got a specific nanobody Nb23-bi, which promoted dehydroepiandrosterone (DHEA)-induced ADGRG2 activation and reversed mutant-induced dysfunctions. By combining structural characterization, crosslinking mass spectrometry, mutational analysis and molecular dynamics simulations, we clarified the allosteric mechanism of how the Nb23-bi modulates conformational changes in the DHEA-binding pocket. Animal studies showed that Nb23-bi promoted the response of DHEA in alleviating testicular inflammation and reversing mutant defects. In summary, we developed an allosteric nanobody of ADGRG2 and gained insights into its functions in reversing disease-associated dysfunctions. Our study may serve as a template for developing allosteric modulators of other aGPCRs for biological and therapeutic purposes.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"43 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979367","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

Small-molecule dissolution of stress granules by redox modulation benefits ALS models 通过氧化还原调节小分子溶解应力颗粒有利于ALS模型

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-14 DOI: 10.1038/s41589-025-01893-5

Hiroyuki Uechi, Sindhuja Sridharan, Jik Nijssen, Jessica Bilstein, Juan M. Iglesias-Artola, Satoshi Kishigami, Virginia Casablancas-Antras, Ina Poser, Eduardo J. Martinez, Edgar Boczek, Michael Wagner, Nadine Tomschke, António M. de Jesus Domingues, Arun Pal, Thom Doeleman, Sukhleen Kour, Eric Nathaniel Anderson, Frank Stein, Hyun O. Lee, Xiaojie Zhang, Anatol W. Fritsch, Marcus Jahnel, Julius Fürsch, Anastasia C. Murthy, Simon Alberti, Marc Bickle, Nicolas L. Fawzi, André Nadler, Della C. David, Udai B. Pandey, Andreas Hermann, Florian Stengel, Benjamin G. Davis, Andrew J. Baldwin, Mikhail M. Savitski, Anthony A. Hyman, Richard J. Wheeler

{"title":"Small-molecule dissolution of stress granules by redox modulation benefits ALS models","authors":"Hiroyuki Uechi, Sindhuja Sridharan, Jik Nijssen, Jessica Bilstein, Juan M. Iglesias-Artola, Satoshi Kishigami, Virginia Casablancas-Antras, Ina Poser, Eduardo J. Martinez, Edgar Boczek, Michael Wagner, Nadine Tomschke, António M. de Jesus Domingues, Arun Pal, Thom Doeleman, Sukhleen Kour, Eric Nathaniel Anderson, Frank Stein, Hyun O. Lee, Xiaojie Zhang, Anatol W. Fritsch, Marcus Jahnel, Julius Fürsch, Anastasia C. Murthy, Simon Alberti, Marc Bickle, Nicolas L. Fawzi, André Nadler, Della C. David, Udai B. Pandey, Andreas Hermann, Florian Stengel, Benjamin G. Davis, Andrew J. Baldwin, Mikhail M. Savitski, Anthony A. Hyman, Richard J. Wheeler","doi":"10.1038/s41589-025-01893-5","DOIUrl":"https://doi.org/10.1038/s41589-025-01893-5","url":null,"abstract":"Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"116 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945701","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

Biosurfactant biosynthesis by Alcanivorax borkumensis and its role in oil biodegradation borkumensis生物表面活性剂的合成及其在石油生物降解中的作用

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-09 DOI: 10.1038/s41589-025-01908-1

Jiaxin Cui, Maximilian Fassl, Vaisnavi Vasanthakumaran, Maya Marita Dierig, Georg Hölzl, Tobias Karmainski, Till Tiso, Sonja Kubicki, Stephan Thies, Lars M. Blank, Karl-Erich Jaeger, Peter Dörmann

{"title":"Biosurfactant biosynthesis by Alcanivorax borkumensis and its role in oil biodegradation","authors":"Jiaxin Cui, Maximilian Fassl, Vaisnavi Vasanthakumaran, Maya Marita Dierig, Georg Hölzl, Tobias Karmainski, Till Tiso, Sonja Kubicki, Stephan Thies, Lars M. Blank, Karl-Erich Jaeger, Peter Dörmann","doi":"10.1038/s41589-025-01908-1","DOIUrl":"https://doi.org/10.1038/s41589-025-01908-1","url":null,"abstract":"The marine bacterium Alcanivorax borkumensis degrades alkanes derived from phytoplankton, natural hydrocarbon seeps and oil spills. We study the biosynthesis and function of a glycine-glucolipid biosurfactant from A. borkumensis for alkane degradation and identify a gene cluster encoding a nonribosomal peptide synthetase, glycosyltransferase and phosphopantetheinyl transferase. Analyses of A. borkumensis mutants and expression studies reveal that the nonribosomal peptide synthetase catalyzes the synthesis of the aglycone (tetra-d-3-hydroxydecanoyl-glycine) from glycine and d-3-hydroxydecanoyl-CoA, to which a glucose moiety is added by the glycosyltransferase. Deficiency in glycine-glucolipid impairs the ability of mutant cells to attach to the oil–water interface, compromises growth on hexadecane and affects carbon storage. The glycine-glucolipid is essential for biofilm formation on oil droplets and uptake of alkanes. The high incidence of Alcanivorax at oil-polluted sites can in part be explained by the accumulation of the glycine-glucolipid on the cell surface, effectively making the cells themselves act as biosurfactants.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"141 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926803","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

Enzymatic combinatorial synthesis of E-64 and related cysteine protease inhibitors 酶法组合合成E-64及相关半胱氨酸蛋白酶抑制剂

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-09 DOI: 10.1038/s41589-025-01907-2

Mengting Liu, Xin Zang, Niko W. Vlahakis, Jose A. Rodriguez, Masao Ohashi, Yi Tang

{"title":"Enzymatic combinatorial synthesis of E-64 and related cysteine protease inhibitors","authors":"Mengting Liu, Xin Zang, Niko W. Vlahakis, Jose A. Rodriguez, Masao Ohashi, Yi Tang","doi":"10.1038/s41589-025-01907-2","DOIUrl":"https://doi.org/10.1038/s41589-025-01907-2","url":null,"abstract":"E-64 is an irreversible cysteine protease inhibitor prominently used in chemical biology and drug discovery. Here we uncover a nonribosomal peptide synthetase-independent biosynthetic pathway for E-64, which is widely conserved in fungi. The pathway starts with epoxidation of fumaric acid to the warhead (2S,3S)-trans-epoxysuccinic acid with an Fe(II)/α-ketoglutarate-dependent oxygenase, followed by successive condensation with an l-amino acid by an adenosine triphosphate grasp enzyme and with an amine by the fungal example of amide bond synthetase. Both amide bond-forming enzymes display notable biocatalytic potential, including scalability, stereoselectivity toward the warhead and broader substrate scopes in forming the amide bonds. Biocatalytic cascade with these amide bond-forming enzymes generated a library of cysteine protease inhibitors, leading to more potent cathepsin inhibitors. Additionally, one-pot reactions enabled the preparative synthesis of clinically relevant inhibitors. Our work highlights the importance of biosynthetic investigation for enzyme discovery and the potential of amide bond-forming enzymes in synthesizing small-molecule libraries.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"66 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926806","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

Chemical Decoding of Spatial Biology 空间生物学的化学解码

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-08 DOI: 10.1038/s41589-025-01910-7

Ziqi Liu, Yan Zhang, Xinyuan Fan, Peng R. Chen

引用次数: 0

Chemically programmable condensates for gene regulation 用于基因调控的化学可编程冷凝物

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-06 DOI: 10.1038/s41589-025-01912-5

引用次数: 0

A heme-dependent enzyme forms the hydrazine in the antibiotic negamycin 一种依赖血红素的酶在抗生素负卡霉素中形成联氨

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-01 DOI: 10.1038/s41589-025-01898-0

Menghua Wang, Zi-Wang Wei, Katherine S. Ryan

{"title":"A heme-dependent enzyme forms the hydrazine in the antibiotic negamycin","authors":"Menghua Wang, Zi-Wang Wei, Katherine S. Ryan","doi":"10.1038/s41589-025-01898-0","DOIUrl":"https://doi.org/10.1038/s41589-025-01898-0","url":null,"abstract":"Negamycin, a hydrazine-containing dipeptide-like antibiotic, was first isolated in 1970 from three strains of Streptomyces purpeofuscus. Its pronounced antibacterial properties render it an appealing candidate for combating multi-drug-resistant Gram-negative bacteria. Additionally, the unique readthrough-promoting activity makes it a subject for research as a potential therapeutic agent for Duchenne muscular dystrophy and other hereditary diseases. Here we use the unusual (R)-β-lysine found in negamycin as a guide to identify the biosynthetic pathway of negamycin and then carry out gene deletion and chemical complementation, stable isotope feeding and enzyme assays to elucidate the key precursors for negamycin assembly. Our work identified NegB as a lysine-2,3-aminomutase that converts lysine into (R)-β-lysine and NegJ as a heme-dependent, N–N bond-forming enzyme. We show that NegJ, together with a ferredoxin encoded outside of the negamycin gene cluster, directly forms hydrazinoacetic acid from glycine and nitrite. NegJ is a novel biocatalyst for N–N bond formation, and our work highlights its potential for genome mining of N–N bond-containing natural products.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"34 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893184","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

Nanometer-resolution tracking of single cargo reveals dynein motor mechanisms. 对单个货物的纳米分辨率追踪揭示了动力蛋白的运动机制。

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-05-01 Epub Date: 2024-08-01 DOI: 10.1038/s41589-024-01694-2

Chunte Sam Peng, Yunxiang Zhang, Qian Liu, G Edward Marti, Yu-Wen Alvin Huang, Thomas C Südhof, Bianxiao Cui, Steven Chu

引用次数: 0