Nature chemical biology最新文献_第3页

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

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