Nature chemical biology最新文献_第6页

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-09-08 DOI: 10.1038/s41589-026-02320-z

Maja Bencun, Etienne Boileau, Christoph Dieterich

引用次数: 0

Chemogenomic maps reveal a PRDX1-dependent iron-damage axis in the DNA damage response. 化学基因组图谱揭示了DNA损伤反应中prdx1依赖的铁损伤轴。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-09-08 DOI: 10.1038/s41589-026-02312-z

Thomas A O'Loughlin, Abolfazl Arab, Sara Misiukiewicz, Elizabeth Montesano, Christopher Yogodzinski, Ashir A Borah, Valentina Quarantotti, Kevin Lou, Barry S Rosen, Jacob E Corn, Davide Gianni, Shaheen Kabir, Josep V Forment, Luke A Gilbert

{"title":"Chemogenomic maps reveal a PRDX1-dependent iron-damage axis in the DNA damage response.","authors":"Thomas A O'Loughlin, Abolfazl Arab, Sara Misiukiewicz, Elizabeth Montesano, Christopher Yogodzinski, Ashir A Borah, Valentina Quarantotti, Kevin Lou, Barry S Rosen, Jacob E Corn, Davide Gianni, Shaheen Kabir, Josep V Forment, Luke A Gilbert","doi":"10.1038/s41589-026-02312-z","DOIUrl":"https://doi.org/10.1038/s41589-026-02312-z","url":null,"abstract":"The DNA damage response (DDR) is a sophisticated network of cellular pathways whose perturbation leads to genome instability and is a key hallmark of oncogenesis. Here, we present data from 32 genome-scale loss-of-function CRISPR interference chemical-genetic screens with inhibitors targeting core constituents of the DDR machinery (PARP, ATR, ATM, DNAPK and WEE1), as both single agents and in combination with poly(ADP-ribose) polymerase inhibitors. These experiments identify >1,000 genes whose perturbation modifies the DDR and provides a rich resource to the DDR community. In addition, this compendium of functional genomics data reveals key principles governing the DDR and highlights a strong chemical-genetic interaction between loss of activity of the peroxiredoxin PRDX1 and all tested DDR inhibitors through a mechanism involving iron availability mediated by an MRGBP-PAX7-IREB2 axis. Our data position PRDX1 as a key suppressor of DNA damage accumulation and potential druggable target in combination with DDR inhibitors.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912878","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

Directed evolution of Lantern enables rapid RNA and protein proximity labeling. 灯笼的定向进化使RNA和蛋白质的快速接近标记。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-09-07 DOI: 10.1038/s41589-026-02313-y

Yuxin Fang, Ziqi Ren, Fu Zheng, Ruixiang Wang, Songrui Zhao, Yihai Zhang, Wentao Wang, Chen Li, Luorong Liu-Yang, Chang Lin, Jun Liu, Peng Zou

{"title":"Directed evolution of Lantern enables rapid RNA and protein proximity labeling.","authors":"Yuxin Fang, Ziqi Ren, Fu Zheng, Ruixiang Wang, Songrui Zhao, Yihai Zhang, Wentao Wang, Chen Li, Luorong Liu-Yang, Chang Lin, Jun Liu, Peng Zou","doi":"10.1038/s41589-026-02313-y","DOIUrl":"https://doi.org/10.1038/s41589-026-02313-y","url":null,"abstract":"In eukaryotic cells, the precise spatial localization of RNAs and proteins is essential for proper cellular function. Genetically encoded photocatalytic proximity labeling techniques have expanded our ability to map subcellular proteomes and transcriptomes, but their temporal resolution remains limited. Here we introduce Lantern, an engineered flavoprotein optimized via directed evolution, which enables sub‑minute, spatially resolved labeling of cellular biomolecules. Lantern is targetable to diverse subcellular compartments, including the endoplasmic reticulum (ER), mitochondria and stress granules (SGs), to map local transcriptomes (CAP-seq) and proteomes (CAP-MS). Using Lantern, we observed that N6-methyladenosine-rich RNAs are recruited to SGs within 10 minutes of stress induction, and ER‑proximal RNAs associate with G3BP1 during early SG assembly. Additionally, Lantern was adapted for cell surface tagging (CAP-CELL), enabling spatially resolved cell typing and identifying cell-cell interactions. Collectively, this study establishes Lantern as a powerful tool that offers unprecedented temporal resolution for investigating the dynamic organization of subcellular molecular networks.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906710","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

Evolving faster proximity chemistry. 进化得更快的接近化学。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-09-07 DOI: 10.1038/s41589-026-02296-w

Shubhashree Pani, Bryan C Dickinson

引用次数: 0

Mechanism of the M. tuberculosis DprE1–DprE2 epimerase complex and inhibition by anti-tubercular drugs 结核分枝杆菌DprE1-DprE2 epimase复合物的机制及抗结核药物的抑制作用。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-09-02 DOI: 10.1038/s41589-026-02317-8

Shan Gao, Fangyu Wu, Yifan Zhang, Sarah M. Batt, Chuancun Wei, Zeyu Wang, Xiuna Yang, Katherine A. Abrahams, Klaus Fütterer, Xinliang Liu, Ping Wang, Gurdyal S. Besra, Zihe Rao, Lu Zhang

{"title":"Mechanism of the M. tuberculosis DprE1–DprE2 epimerase complex and inhibition by anti-tubercular drugs","authors":"Shan Gao, Fangyu Wu, Yifan Zhang, Sarah M. Batt, Chuancun Wei, Zeyu Wang, Xiuna Yang, Katherine A. Abrahams, Klaus Fütterer, Xinliang Liu, Ping Wang, Gurdyal S. Besra, Zihe Rao, Lu Zhang","doi":"10.1038/s41589-026-02317-8","DOIUrl":"10.1038/s41589-026-02317-8","url":null,"abstract":"Pretomanid and delamanid are prodrugs, whose active derivatives have been reported to target decaprenylphosphoribose-2′-reductase, DprE2, while quabodepistat is a noncovalent inhibitor of decaprenylphosphoribose-2′-oxidase, DprE1. Both enzymes are involved in Mycobacterium tuberculosis cell wall synthesis, but the mechanism of the DprE1–DprE2 epimerase complex and its inhibition by these compounds remain unclear. We report cryo-EM structures of the M. tuberculosis DprE1–DprE2 complex bound with either substrate or quabodepistat in DprE1, and with either activated pretomanid or delamanid in DprE2, respectively. DprE1–DprE2 assembles as a membrane-associated tetramer of a DprE2 dimer flanked on each side by a DprE1 subunit. Both pretomanid and delamanid bind to DprE2 in an NADH-adduct form and within a conserved binding pocket that extends from the NADH-binding site to the substrate-binding site. Quabodepistat binds to DprE1 with a unique mode. Our data reveal the mode of action of these drugs, allowing rational design of new derivatives for improved tuberculosis treatments. Pretomanid and delamanid are prodrugs reported to target the decaprenylphosphoribose-2′-reductase DprE2, while the noncovalent inhibitor quabodepistat has been reported to target the decaprenylphosphoribose-2′-oxidase DprE1, with both enzymes involved in Mycobacterium tuberculosis cell wall biosynthesis. Now, cryo-EM structures reveal the mechanism of the DprE1–DprE2 epimerase complex and its inhibition by these drugs.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 11","pages":"1834-1842"},"PeriodicalIF":15.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881198","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

α2,6-Sialoglycan-regulated antitumor immunity of tumor-infiltrating CD8+ T cells α2,6-唾液聚糖调控肿瘤浸润性CD8+ T细胞的抗肿瘤免疫。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-09-01 DOI: 10.1038/s41589-026-02299-7

Shuyu Liang, Qi Tang, Yilan Guo, Shaoran Zhang, Qitao Song, Peng Dai, Xing Chen

{"title":"α2,6-Sialoglycan-regulated antitumor immunity of tumor-infiltrating CD8+ T cells","authors":"Shuyu Liang, Qi Tang, Yilan Guo, Shaoran Zhang, Qitao Song, Peng Dai, Xing Chen","doi":"10.1038/s41589-026-02299-7","DOIUrl":"10.1038/s41589-026-02299-7","url":null,"abstract":"Cell-surface sialoglycans overexpressed on cancer cells suppress activation of tumor-infiltrating immune cells (TIICs) and thus represent promising targets for cancer immunotherapy. However, the functional roles of sialylation in TIICs remain incompletely understood. Here we developed a strategy for single-cell correlative analysis of α2,3- and α2,6-linked sialoglycans and transcriptomes to determine the correlations of cell-surface sialylation with gene expression of the same cells in a linkage-specific manner by single-cell RNA sequencing. We found that α2,3- and α2,6-sialoglycans were distinctively regulated across specific TIIC subpopulations in murine tumors. Notably, downregulation of α2,6-sialoglycans was identified as a cell-surface marker for intratumoral tumor-specific antigen-reactive CD8+ T cells with high avidity. Mechanistically, high-avidity (but not low-avidity) activation of murine CD8+ T cells within the tumor suppressed β-galactoside α2,6-sialyltransferase 1 expression, which downregulates α2,6-sialylation and exposes galectin-1 ligands. Functionally, galectin-1 binding promoted T cell apoptosis and immune evasion in cancer. This work demonstrates the functional significance and therapeutic potential of specific sialoglycans on TIICs. Although hypersialylation on cancer cells and its roles in immune evasion and metastasis are well known, the functional roles of cell-surface sialylation on tumor-infiltrating immune cells (TIICs) are not completely understood. Now an α2,3- or α2,6-sialoglycan linkage-specific barcoding and single-cell RNA sequencing approach reveals differential regulation of α2,3- and α2,6-sialylation in subpopulations of TIICs and correlates sialylation with TIIC phenotypes and functions.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 11","pages":"1810-1821"},"PeriodicalIF":15.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875402","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

Adaptive mechanisms and emerging cancer therapeutics for CDK2 inhibitors. CDK2抑制剂的适应性机制和新出现的癌症治疗方法。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-08-31 DOI: 10.1038/s41589-026-02307-w

Changhao He, Kevan M Shokat

引用次数: 0

An enantioselective covalent inhibitor of BAX confers cytoprotection in vivo. BAX的对映选择性共价抑制剂在体内具有细胞保护作用。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-08-28 DOI: 10.1038/s41589-026-02297-9

Peiwen Shi, Bruno Melillo, Matthew W McHenry, Christina M Camara, Ka Yang, Evert Njomen, Marina Godes, Maria F Pazyra-Murphy, Mary Rose Branch, Bethany Tesar, Rosalind A Segal, Lee L Rubin, Michael D Cameron, Gregory H Bird, Thomas E Wales, Steven P Gygi, Benjamin F Cravatt, Loren D Walensky

{"title":"An enantioselective covalent inhibitor of BAX confers cytoprotection in vivo.","authors":"Peiwen Shi, Bruno Melillo, Matthew W McHenry, Christina M Camara, Ka Yang, Evert Njomen, Marina Godes, Maria F Pazyra-Murphy, Mary Rose Branch, Bethany Tesar, Rosalind A Segal, Lee L Rubin, Michael D Cameron, Gregory H Bird, Thomas E Wales, Steven P Gygi, Benjamin F Cravatt, Loren D Walensky","doi":"10.1038/s41589-026-02297-9","DOIUrl":"https://doi.org/10.1038/s41589-026-02297-9","url":null,"abstract":"No therapies directly block apoptosis in tissue injury or the many diseases driven by cell loss. The BCL-2 family protein BAX is a central mediator of this pathway and C126 resides within a key regulatory region where physiologic or pharmacologic ligands can activate or inhibit its function. Here, we report enantioselective covalent BAX inhibitors that site-specifically react with C126 and confer cytoprotection across multiple cell types. These ligands constrain BAX conformation and suppress apoptosis in a strictly BAX-dependent manner. Medicinal chemistry optimization yielded covalent BAX inhibitor 3 (CBI-3), an analog with pharmacokinetics suitable for in vivo studies. In a murine model of Fas-induced fulminant hepatic failure, CBI-3 reduced hepatocyte apoptosis and preserved liver histology and survival. CBI-3 also conferred cytoprotection of motor neurons derived from human induced pluripotent stem cells of healthy and amyotrophic lateral sclerosis donors. These findings establish covalent BAX inhibition as a therapeutic strategy to directly block pathologic cell death.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850997","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 safety pin against BAX. 防止BAX的安全别针。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-08-28 DOI: 10.1038/s41589-026-02301-2

Tudor Moldoveanu

引用次数: 0

Topogenic sequence recognition at TIM complexes revealed by a stendomycin-bound structure 司度霉素结合结构揭示的TIM复合物的拓扑序列识别。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-08-26 DOI: 10.1038/s41589-026-02304-z

Yuanyuan Chen, Antony Lurie, Kevin Wu, Kihong Nam, Samantha N. Garcia, Nathaniel W. M. Dempsey, Esben B. Svenningsen, Thomas Tørring, Thomas B. Poulsen, Alban Ordureau, Eunyong Park

{"title":"Topogenic sequence recognition at TIM complexes revealed by a stendomycin-bound structure","authors":"Yuanyuan Chen, Antony Lurie, Kevin Wu, Kihong Nam, Samantha N. Garcia, Nathaniel W. M. Dempsey, Esben B. Svenningsen, Thomas Tørring, Thomas B. Poulsen, Alban Ordureau, Eunyong Park","doi":"10.1038/s41589-026-02304-z","DOIUrl":"10.1038/s41589-026-02304-z","url":null,"abstract":"In the mitochondrial inner membrane (IM), topogenesis of imported proteins is mediated by TIM23 and TIM22 complexes. TIM23 translocates soluble polypeptides across the IM into the matrix, whereas TIM22 inserts polytopic membrane proteins into the IM. Although functionally distinct, both rely on homologous subunits, Tim17 in TIM23 and Tim22 in TIM22. The underlying mechanisms, however, remain elusive. Here we use structural and functional approaches with yeast Tim17, Tim22 and the TIM23 inhibitor stendomycin. Cryogenic-electron microscopy shows that stendomycin binds to the protein translocation cavity of Tim17, mimicking α-helical topogenic sequences. While Tim22 does not bind stendomycin, a single mutation in its equivalent cavity suffices to enable binding. The cavities of Tim17 and Tim22 are largely interchangeable without disrupting their functions. Lastly, stendomycin triggers a collapse of the membrane potential, likely via its Tim17- or Tim22-dependent translocation across the IM. These findings reveal a mechanistic overlap between protein translocases and insertases. The mitochondrial inner membrane complexes TIM23 and TIM22 mediate distinct protein topogenesis functions in polypeptide import. The authors reveal their mechanistic overlap in topogenic sequence recognition by cryo-EM and functional studies using the yeast system and the stendomycin inhibitor.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 11","pages":"1863-1874"},"PeriodicalIF":15.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41589-026-02304-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148830583","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