Nature chemical biology最新文献_第3页

Rolling toward circular solutions 滚向圆形解

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-23 DOI: 10.1038/s41589-025-01837-z

Yiyun Song

引用次数: 0

TRIMming the nuclear pore 修整核孔

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-23 DOI: 10.1038/s41589-025-01838-y

Grant Miura

引用次数: 0

Hashing the message with cells 用单元格对消息进行散列

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-20 DOI: 10.1038/s41589-024-01830-y

Jongmin Kim, Elisa Franco

引用次数: 0

Continuous selection in E. coli to identify cyclic peptide inhibitors of protein aggregation 连续筛选大肠杆菌中环状肽蛋白聚集抑制剂的鉴定

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-17 DOI: 10.1038/s41589-024-01824-w

引用次数: 0

A DNA phosphorothioation pathway via adenylated intermediate modulates Tdp machinery DNA磷酸化途径通过腺苷化中间体调节Tdp机制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-16 DOI: 10.1038/s41589-024-01832-w

Tianchen An, Qian Tan, Lixu Jiang, Li Liu, Xing Jiang, Liying Liu, Xiaofei Chang, Xihao Tian, Zixin Deng, Shuai Gao, Lianrong Wang, Shi Chen

{"title":"A DNA phosphorothioation pathway via adenylated intermediate modulates Tdp machinery","authors":"Tianchen An, Qian Tan, Lixu Jiang, Li Liu, Xing Jiang, Liying Liu, Xiaofei Chang, Xihao Tian, Zixin Deng, Shuai Gao, Lianrong Wang, Shi Chen","doi":"10.1038/s41589-024-01832-w","DOIUrl":"https://doi.org/10.1038/s41589-024-01832-w","url":null,"abstract":"In prokaryotes, the non-bridging oxygen in the DNA sugar-phosphate backbone can be enzymatically replaced by a sulfur atom, resulting in phosphorothioate (PT) modification. However, the mechanism underlying the oxygen-to-sulfur substitution remains enigmatic. In this study, we discovered a hypercompact DNA phosphorothioation system, TdpABC, in extreme thermophiles. This DNA sulfuration process occurs through two sequential steps: an initial activation step by ATP to form an adenylated intermediate, followed by a substitution step where the adenyl group is replaced with a sulfur atom. Together with the TdpA–TdpB, the TdpABC system provides anti-phage defense by degrading PT-free phage DNA. Cryogenic electron microscopy structural analysis revealed that the TdpA hexamer binds one strand of encircled duplex DNA via hydrogen bonds arranged in a spiral staircase conformation. Nevertheless, the TdpAB–DNA interaction was sensitive to the hydrophobicity of the PT sulfur. PTs inhibit ATP-driven translocation and nuclease activity of TdpAB on self-DNA, thereby preventing autoimmunity.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"15 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986759","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

PROTAR Vaccine 2.0 generates influenza vaccines by degrading multiple viral proteins PROTAR疫苗2.0通过降解多种病毒蛋白产生流感疫苗

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-15 DOI: 10.1038/s41589-024-01813-z

Chunhe Zhang, Jihuan Hou, Zhen Li, Quan Shen, Haiqing Bai, Li Chen, Jinying Shen, Ping Wang, Yinlei Su, Jing Li, Qisi Zhang, Chengyao Liu, Xuetong Xi, Fei Qi, Yuting Chen, Xin Xie, Adam Yongxin Ye, Xiaoheng Liu, Roberto Plebani, George Church, Longlong Si

{"title":"PROTAR Vaccine 2.0 generates influenza vaccines by degrading multiple viral proteins","authors":"Chunhe Zhang, Jihuan Hou, Zhen Li, Quan Shen, Haiqing Bai, Li Chen, Jinying Shen, Ping Wang, Yinlei Su, Jing Li, Qisi Zhang, Chengyao Liu, Xuetong Xi, Fei Qi, Yuting Chen, Xin Xie, Adam Yongxin Ye, Xiaoheng Liu, Roberto Plebani, George Church, Longlong Si","doi":"10.1038/s41589-024-01813-z","DOIUrl":"https://doi.org/10.1038/s41589-024-01813-z","url":null,"abstract":"Manipulating viral protein stability using the cellular ubiquitin-proteasome system (UPS) represents a promising approach for developing live-attenuated vaccines. The first-generation proteolysis-targeting (PROTAR) vaccine had limitations, as it incorporates proteasome-targeting degrons (PTDs) at only the terminal ends of viral proteins, potentially restricting its broad application. Here we developed the next-generation PROTAR vaccine approach, referred to as PROTAR 2.0, which enabled flexible incorporation of PTDs at various genomic loci of influenza viruses, including internal regions and terminal ends. The PROTAR 2.0 influenza viruses maintained efficient replication in UPS-deficient cells for large-scale production but were attenuated by PTD-mediated proteasomal degradation of viral proteins in conventional cells. Incorporation of multiple PTDs into one virus generated optimized PROTAR 2.0 vaccine candidates. In animal models, PROTAR 2.0 vaccine candidates were highly attenuated and a single-dose intranasal immunization induced robust and broad immune responses that provided complete cross-reactive protection against both homologous and heterologous viral challenges.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"1 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981369","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

Orthogonalized human protease control of secreted signals 正交化人蛋白酶控制分泌信号

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-15 DOI: 10.1038/s41589-024-01831-x

Carlos A. Aldrete, Connor C. Call, Lucas E. Sant’Anna, Alexander E. Vlahos, Jimin Pei, Qian Cong, Xiaojing J. Gao

{"title":"Orthogonalized human protease control of secreted signals","authors":"Carlos A. Aldrete, Connor C. Call, Lucas E. Sant’Anna, Alexander E. Vlahos, Jimin Pei, Qian Cong, Xiaojing J. Gao","doi":"10.1038/s41589-024-01831-x","DOIUrl":"https://doi.org/10.1038/s41589-024-01831-x","url":null,"abstract":"Synthetic circuits that regulate protein secretion in human cells could support cell-based therapies by enabling control over local environments. Although protein-level circuits enable such potential clinical applications, featuring orthogonality and compactness, their non-human origin poses a potential immunogenic risk. In this study, we developed Humanized Drug Induced Regulation of Engineered CyTokines (hDIRECT) as a platform to control cytokine activity exclusively using human-derived proteins. We sourced a specific human protease and its FDA-approved inhibitor. We engineered cytokines (IL-2, IL-6 and IL-10) whose activities can be activated and abrogated by proteolytic cleavage. We used species specificity and re-localization strategies to orthogonalize the cytokines and protease from the human context that they would be deployed in. hDIRECT should enable local cytokine activation to support a variety of cell-based therapies, such as muscle regeneration and cancer immunotherapy. Our work offers a proof of concept for the emerging appreciation of humanization in synthetic biology for human health.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"36 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981370","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 inhibits KCNQ channels with a non-blocking mechanism 小分子以非阻断机制抑制KCNQ通道

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-15 DOI: 10.1038/s41589-024-01834-8

Junnan Li, Zhenni Yang, Shaoying Zhang, Yangliang Ye, Jiangnan He, Yan Zhang, Huayun Han, Wan Kong, Jiangru Liu, Yu Min, Juwen Shen, Lianghe Mei, Zongsheng Chen, Panpan Hou, Jiangtao Guo, Qiansen Zhang, Huaiyu Yang

{"title":"Small molecule inhibits KCNQ channels with a non-blocking mechanism","authors":"Junnan Li, Zhenni Yang, Shaoying Zhang, Yangliang Ye, Jiangnan He, Yan Zhang, Huayun Han, Wan Kong, Jiangru Liu, Yu Min, Juwen Shen, Lianghe Mei, Zongsheng Chen, Panpan Hou, Jiangtao Guo, Qiansen Zhang, Huaiyu Yang","doi":"10.1038/s41589-024-01834-8","DOIUrl":"https://doi.org/10.1038/s41589-024-01834-8","url":null,"abstract":"Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction and neurological diseases, highlighting the importance of identifying modulators with distinct mechanisms. Here we report two small-molecule modulators with the same chemical scaffold, Ebio2 and Ebio3, targeting a potassium channel KCNQ2, with opposite effects: Ebio2 acts as a potent activator, whereas Ebio3 serves as a potent and selective inhibitor. Guided by cryogenic electron microscopy, patch-clamp recordings and molecular dynamics simulations, we reveal that Ebio3 attaches to the outside of the inner gate, employing a unique non-blocking inhibitory mechanism that directly squeezes the S6 pore helix to inactivate the KCNQ2 channel. Ebio3 also showed efficacy in inhibiting currents of KCNQ2 pathogenic gain-of-function mutations, presenting an avenue for VGIC-targeted therapies. Overall, these findings contribute to the understanding of KCNQ2 inhibition and provide insights into developing selective, non-blocking VGIC inhibitors.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"28 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981368","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

Aromatic side-chain crosslinking in RiPP biosynthesis 芳香侧链交联在RiPP生物合成中的应用

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-15 DOI: 10.1038/s41589-024-01795-y

Sanath K. Kandy, Michael A. Pasquale, Jonathan R. Chekan

{"title":"Aromatic side-chain crosslinking in RiPP biosynthesis","authors":"Sanath K. Kandy, Michael A. Pasquale, Jonathan R. Chekan","doi":"10.1038/s41589-024-01795-y","DOIUrl":"10.1038/s41589-024-01795-y","url":null,"abstract":"Peptide cyclization is a defining feature of many bioactive molecules, particularly in the ribosomally synthesized and post-translationally modified peptide (RiPP) family of natural products. Although enzymes responsible for N- to C-terminal macrocyclization, lanthipeptide formation or heterocycle installation have been well documented, a diverse array of cyclases have been discovered that perform crosslinking of aromatic side chains. These enzymes form either biaryl linkages between two aromatic amino acids or a crosslink between one aliphatic amino acid and one aromatic amino acid. Incredibly, nature has evolved multiple routes to install these crosslinks. While enzymes such as cytochromes P450 and radical S-adenosylmethionine (rSAM) enzymes are well known from other pathways, this role in RiPP biosynthesis has only recently been appreciated. Others, such as burpitide cyclases and DUF3328 (UstY) family proteins, come from eukaryotes and are relatively uncharacterized enzyme classes. This Review covers the emerging theme of aromatic amino acid side-chain crosslinking in RiPPs by focusing on the newly discovered enzymes responsible for catalyzing these challenging reactions. Aromatic side-chain crosslinking is emerging as a widespread and biosynthetically diverse feature in the RiPP natural products. This Review summarizes and unifies recent advancements, focusing on key enzymes that catalyze these modifications.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 2","pages":"168-181"},"PeriodicalIF":12.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981685","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

Catalytic-independent functions of the Integrator–PP2A complex (INTAC) confer sensitivity to BET inhibition Integrator-PP2A复合物（INTAC）的催化独立功能赋予了BET抑制的敏感性

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-14 DOI: 10.1038/s41589-024-01807-x

Pengyu Fan, Xue-Ying Shang, Aixia Song, Shuo Chen, Run-Yuan Mao, Jingchuan Ma, Jiwei Chen, Zhenning Wang, Hai Zheng, Bolin Tao, Lei Hong, Jiaxian Liu, Wei Xu, Wei Jiang, Hongjie Shen, Qi Zhang, Huijuan Yang, Xiao-Ming Meng, Fei Lan, Jingdong Cheng, Congling Xu, Peng Zhang, Hai Jiang, Fei Xavier Chen

{"title":"Catalytic-independent functions of the Integrator–PP2A complex (INTAC) confer sensitivity to BET inhibition","authors":"Pengyu Fan, Xue-Ying Shang, Aixia Song, Shuo Chen, Run-Yuan Mao, Jingchuan Ma, Jiwei Chen, Zhenning Wang, Hai Zheng, Bolin Tao, Lei Hong, Jiaxian Liu, Wei Xu, Wei Jiang, Hongjie Shen, Qi Zhang, Huijuan Yang, Xiao-Ming Meng, Fei Lan, Jingdong Cheng, Congling Xu, Peng Zhang, Hai Jiang, Fei Xavier Chen","doi":"10.1038/s41589-024-01807-x","DOIUrl":"https://doi.org/10.1038/s41589-024-01807-x","url":null,"abstract":"Chromatin and transcription regulators are critical to defining cell identity through shaping epigenetic and transcriptional landscapes, with their misregulation being closely linked to oncogenesis. Pharmacologically targeting these regulators, particularly the transcription-activating BET proteins, has emerged as a promising approach in cancer therapy, yet intrinsic or acquired resistance frequently occurs, with poorly understood mechanisms. Here, using genome-wide CRISPR screens, we find that BET inhibitor efficacy in mediating transcriptional silencing and growth inhibition depends on the auxiliary/arm/tail module of the Integrator–PP2A complex (INTAC), a global regulator of RNA polymerase II pause–release dynamics. This process bypasses a requirement for the catalytic activities of INTAC and instead leverages direct engagement of the auxiliary module with the RACK7/ZMYND8–KDM5C complex to remove histone H3K4 methylation. Targeted degradation of the COMPASS subunit WDR5 to attenuate H3K4 methylation restores sensitivity to BET inhibitors, highlighting how simultaneously targeting coordinated chromatin and transcription regulators can circumvent drug-resistant tumors.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"97 5 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974843","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