Nature chemical biology最新文献

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

Fishing for covalent peptides 寻找共价肽

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-05-01 DOI: 10.1038/s41589-025-01903-6

Guoqing Jin

引用次数: 0

Facile generation of drug-like conformational antibodies specific for amyloid fibrils 针对淀粉样原纤维的药物样构象抗体的快速生成

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-29 DOI: 10.1038/s41589-025-01881-9

Alec A. Desai, Jennifer M. Zupancic, Hanna Trzeciakiewicz, Julia E. Gerson, Kelly N. DuBois, Mary E. Skinner, Lisa M. Sharkey, Nikki McArthur, Sean P. Ferris, Nemil N. Bhatt, Emily K. Makowski, Matthew D. Smith, Hongwei Chen, Jie Huang, Cynthia Jerez, Yun-Huai Kuo, Ravi S. Kane, Nicholas M. Kanaan, Henry L. Paulson, Peter M. Tessier

{"title":"Facile generation of drug-like conformational antibodies specific for amyloid fibrils","authors":"Alec A. Desai, Jennifer M. Zupancic, Hanna Trzeciakiewicz, Julia E. Gerson, Kelly N. DuBois, Mary E. Skinner, Lisa M. Sharkey, Nikki McArthur, Sean P. Ferris, Nemil N. Bhatt, Emily K. Makowski, Matthew D. Smith, Hongwei Chen, Jie Huang, Cynthia Jerez, Yun-Huai Kuo, Ravi S. Kane, Nicholas M. Kanaan, Henry L. Paulson, Peter M. Tessier","doi":"10.1038/s41589-025-01881-9","DOIUrl":"https://doi.org/10.1038/s41589-025-01881-9","url":null,"abstract":"Antibodies that recognize insoluble antigens, such as amyloid fibrils associated with neurodegenerative disorders, are important for research, diagnostic and therapeutic applications. However, these types of antibodies are difficult to generate, typically require animal immunization and also commonly require humanization in the case of therapeutic applications. Here we report a methodology for generating high-quality, fully human, conformation-specific antibodies against amyloid fibrils using a published human nonimmune library, yeast-surface display and quantitative fluorescence-activated cell sorting. Notably, this approach enables the isolation of conformation-specific antibodies against tau fibrils (Alzheimer’s disease) and α-synuclein fibrils (Parkinson’s disease) with combinations of high affinity, high conformational specificity and, in some cases, low off-target binding that rival or exceed those of clinical-stage antibodies specific for tau (zagotenemab) and α-synuclein (cinpanemab). This approach is expected to simplify the generation of conformation-specific antibodies against diverse protein aggregates and other insoluble antigens.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"18 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884841","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

Monitoring in real time and far-red imaging of H2O2 dynamics with subcellular resolution 实时监测和亚细胞分辨率的H2O2动态远红成像

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-28 DOI: 10.1038/s41589-025-01891-7

Justin Daho Lee, Amanda Nguyen, Chelsea E. Gibbs, Zheyu Ruby Jin, Yuxuan Wang, Aida Moghadasi, Sarah J. Wait, Hojun Choi, Kira M. Evitts, Anthony Asencio, Samantha B. Bremner, Shani Zuniga, Vedant Chavan, Inez K. A. Pranoto, C. Andrew Williams, Annette Smith, Farid Moussavi-Harami, Michael Regnier, David Baker, Jessica E. Young, David L. Mack, Elizabeth Nance, Patrick M. Boyle, Andre Berndt

{"title":"Monitoring in real time and far-red imaging of H2O2 dynamics with subcellular resolution","authors":"Justin Daho Lee, Amanda Nguyen, Chelsea E. Gibbs, Zheyu Ruby Jin, Yuxuan Wang, Aida Moghadasi, Sarah J. Wait, Hojun Choi, Kira M. Evitts, Anthony Asencio, Samantha B. Bremner, Shani Zuniga, Vedant Chavan, Inez K. A. Pranoto, C. Andrew Williams, Annette Smith, Farid Moussavi-Harami, Michael Regnier, David Baker, Jessica E. Young, David L. Mack, Elizabeth Nance, Patrick M. Boyle, Andre Berndt","doi":"10.1038/s41589-025-01891-7","DOIUrl":"https://doi.org/10.1038/s41589-025-01891-7","url":null,"abstract":"Monitoring H2O2 dynamics in conjunction with key biological interactants is critical for elucidating the physiological outcome of cellular redox regulation. Optogenetic hydrogen peroxide sensor with HaloTag with JF635 (oROS-HT635) allows fast and sensitive chemigenetic far-red H2O2 imaging while overcoming drawbacks of existing red fluorescent H2O2 indicators, including oxygen dependency, high pH sensitivity, photoartifacts and intracellular aggregation. The compatibility of oROS-HT635 with blue-green-shifted optical tools allows versatile optogenetic dissection of redox biology. In addition, targeted expression of oROS-HT635 and multiplexed H2O2 imaging enables spatially resolved imaging of H2O2 targeting the plasma membrane and neighboring cells. Here we present multiplexed use cases of oROS-HT635 with other green fluorescence reporters by capturing acute and real-time changes in H2O2 with intracellular redox potential and Ca2+ levels in response to auranofin, an inhibitor of antioxidative enzymes, via dual-color imaging. oROS-HT635 enables detailed insights into intricate intracellular and intercellular H2O2 dynamics, along with their interactants, through spatially resolved, far-red H2O2 imaging in real time.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"11 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880396","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

Interfering with GPX4 degradation 干扰GPX4降解

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-25 DOI: 10.1038/s41589-025-01873-9

Jing Li, Yuhan Zhou, Weimin Wang

引用次数: 0

Domain coupling in activation of a family C GPCR C家族GPCR激活中的结构域偶联

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-25 DOI: 10.1038/s41589-025-01895-3

Naomi R. Latorraca, Sam Sabaat, Chris H. Habrian, Julia Bleier, Cherise Stanley, Colin D. Kinz-Thompson, Susan Marqusee, Ehud Y. Isacoff

{"title":"Domain coupling in activation of a family C GPCR","authors":"Naomi R. Latorraca, Sam Sabaat, Chris H. Habrian, Julia Bleier, Cherise Stanley, Colin D. Kinz-Thompson, Susan Marqusee, Ehud Y. Isacoff","doi":"10.1038/s41589-025-01895-3","DOIUrl":"https://doi.org/10.1038/s41589-025-01895-3","url":null,"abstract":"The G protein-coupled metabotropic glutamate receptors form homodimers and heterodimers with highly diverse responses to glutamate and varying physiological functions. We employ molecular dynamics, single-molecule spectroscopy and hydrogen–deuterium exchange to dissect the activation pathway triggered by glutamate. We find that activation entails multiple loosely coupled steps, including formation of an agonist-bound, pre-active intermediate whose transition to active conformations forms dimerization interface contacts that set efficacy. The agonist-bound receptor populates at least two additional intermediates en route to G protein-coupling conformations. Sequential transitions into these states act as ‘gates’, which attenuate the effects of glutamate. Thus, the agonist-bound receptor is remarkably dynamic, with low occupancy of G protein-coupling conformations, providing considerable headroom for modulation by allosteric ligands. Sequence variation within the dimerization interface, as well as altered conformational coupling in receptor heterodimers, may contribute to precise decoding of glutamate signals over broad spatial and temporal scales.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"26 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872489","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

PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation PSAT1损害铁下垂并通过GPX4羟基化降低免疫治疗效果

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-25 DOI: 10.1038/s41589-025-01887-3

Peixiang Zheng, Zhiqiang Hu, Yuli Shen, Lina Gu, Yuan Ouyang, Yuran Duan, Guimei Ji, Bofei Dong, Yanni Lin, Ting Wen, Qi Tian, Yueru Hou, Qimin Zhou, Xue Sun, Xiaohan Chen, Katherine L. Wang, Shudi Luo, Shiqi Wu, Yuening Sun, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Zheng Wang, Xueli Bai, Shengzhong Duan, Yuan Ding, Yanli Bi, Yuhao Wang, Gaopeng Li, Xiaoguang Liu, Zhimin Lu, Xiaohong Wu, Zhiyuan Tang, Daqian Xu

{"title":"PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation","authors":"Peixiang Zheng, Zhiqiang Hu, Yuli Shen, Lina Gu, Yuan Ouyang, Yuran Duan, Guimei Ji, Bofei Dong, Yanni Lin, Ting Wen, Qi Tian, Yueru Hou, Qimin Zhou, Xue Sun, Xiaohan Chen, Katherine L. Wang, Shudi Luo, Shiqi Wu, Yuening Sun, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Zheng Wang, Xueli Bai, Shengzhong Duan, Yuan Ding, Yanli Bi, Yuhao Wang, Gaopeng Li, Xiaoguang Liu, Zhimin Lu, Xiaohong Wu, Zhiyuan Tang, Daqian Xu","doi":"10.1038/s41589-025-01887-3","DOIUrl":"https://doi.org/10.1038/s41589-025-01887-3","url":null,"abstract":"Tumor cells adapt to the inflammatory tumor microenvironment (TME) and develop resistance to immunotherapy, with ferroptosis being a major form of tumor cell death. However, the mechanisms by which tumor cells coordinate TME stimuli and their unique metabolic traits to evade ferroptosis and develop resistance to immunotherapy remain unclear. Here we showed that interferon-γ (IFNγ)-activated calcium/calmodulin-dependent protein kinase II phosphorylates phosphoserine aminotransferase 1 (PSAT1) at serine 337 (S337), allowing it to interact with glutathione peroxidase 4 (GPX4) and stabilize the protein, counteracting ferroptosis. PSAT1 elevates GPX4 stability by promoting α-ketoglutarate-dependent PHD3-mediated GPX4 proline 159 (P159) hydroxylation, disrupting its binding to HSC70 and inhibiting autophagy-mediated degradation. In mice, reconstitution of PSAT1 S337A or GPX4 P159A promotes ferroptosis and suppresses triple-negative breast cancer (TNBC) progression. Blocking PSAT1 pS337 with CPP elevates IFNγ-induced ferroptosis and enhances the efficacy of programmed cell death protein 1 (PD-1) antibodies in TNBC. Additionally, PSAT1-mediated GPX4 hydroxylation correlates with poor immunotherapy outcomes in patients with TNBC, highlighting PSAT1’s noncanonical role in suppressing ferroptosis and immunotherapy sensitivity.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"33 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872514","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

Advances in uncovering the mechanisms of macromolecular conformational entropy 大分子构象熵机制的研究进展

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-24 DOI: 10.1038/s41589-025-01879-3

Stephanie A. Wankowicz, James S. Fraser

{"title":"Advances in uncovering the mechanisms of macromolecular conformational entropy","authors":"Stephanie A. Wankowicz, James S. Fraser","doi":"10.1038/s41589-025-01879-3","DOIUrl":"https://doi.org/10.1038/s41589-025-01879-3","url":null,"abstract":"During protein folding, proteins transition from a disordered polymer into a globular structure, markedly decreasing their conformational degrees of freedom, leading to a substantial reduction in entropy. Nonetheless, folded proteins retain substantial entropy as they fluctuate between the conformations that make up their native state. This residual entropy contributes to crucial functions like binding and catalysis, supported by growing evidence primarily from NMR and simulation studies. Here, we propose three major ways that macromolecules use conformational entropy to perform their functions; first, prepaying entropic cost through ordering of the ground state; second, spatially redistributing entropy, in which a decrease in entropy in one area is reciprocated by an increase in entropy elsewhere; third, populating catalytically competent ensembles, in which conformational entropy within the enzymatic scaffold aids in lowering transition state barriers. We also provide our perspective on how solving the current challenge of structurally defining the ensembles encoding conformational entropy will lead to new possibilities for controlling binding, catalysis and allostery.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866153","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

TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6 TOM20驱动的E3连接酶招募通过PLD6调节线粒体动力学

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-22 DOI: 10.1038/s41589-025-01894-4

Anat Raiff, Shidong Zhao, Aizat Bekturova, Colin Zenge, Shir Mazor, Xinyan Chen, Wenwen Ru, Yaara Makaros, Tslil Ast, Alban Ordureau, Chao Xu, Itay Koren

{"title":"TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6","authors":"Anat Raiff, Shidong Zhao, Aizat Bekturova, Colin Zenge, Shir Mazor, Xinyan Chen, Wenwen Ru, Yaara Makaros, Tslil Ast, Alban Ordureau, Chao Xu, Itay Koren","doi":"10.1038/s41589-025-01894-4","DOIUrl":"https://doi.org/10.1038/s41589-025-01894-4","url":null,"abstract":"Mitochondrial homeostasis is maintained through complex regulatory mechanisms, including the balance of mitochondrial dynamics involving fusion and fission processes. A central player in this regulation is the ubiquitin–proteasome system (UPS), which controls the degradation of pivotal mitochondrial proteins. In this study, we identified cullin–RING E3 ligase 2 (CRL2) and its substrate receptor, FEM1B, as critical regulators of mitochondrial dynamics. Through proteomic analysis, we demonstrate here that FEM1B controls the turnover of PLD6, a key regulator of mitochondrial dynamics. Using structural and biochemical approaches, we show that FEM1B physically interacts with PLD6 and that this interaction is facilitated by the direct association of FEM1B with the mitochondrial import receptor TOM20. Ablation of FEM1B or disruption of the FEM1B–TOM20 interaction impairs PLD6 degradation and induces mitochondrial defects, phenocopying PLD6 overexpression. These findings underscore the importance of FEM1B in maintaining mitochondrial morphology and provide further mechanistic insights into how the UPS regulates mitochondrial homeostasis.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"63 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857450","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

Peptide surfactants with post-translational C-methylations that promote bacterial development 翻译后c -甲基化的肽表面活性剂促进细菌发育

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-04-22 DOI: 10.1038/s41589-025-01882-8

Chen Zhang, Yuchen Li, Ellysia N. Overton, Mohammad R. Seyedsayamdost

引用次数: 0