Nature chemical biology最新文献_第2页

Reduction reporter 减少记者。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-10-19 DOI: 10.1038/s41589-026-02364-1

Grant Miura

引用次数: 0

Tryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1-HSPA9 complex. 色氨酸立体探针鉴定GRPEL1-HSPA9复合物的抑制剂。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-10-16 DOI: 10.1038/s41589-026-02348-1

Rachel E Hayward, Raymond F Berkeley, Zijian Gao, Maximilian Garhammer, Marc A Morizono, Evert Njomen, Haoxin Li, Kristen E DeMeester, Victor Cociorva, Mark A Herzik, F Ulrich Hartl, Bruno Melillo, Benjamin F Cravatt

{"title":"Tryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1-HSPA9 complex.","authors":"Rachel E Hayward, Raymond F Berkeley, Zijian Gao, Maximilian Garhammer, Marc A Morizono, Evert Njomen, Haoxin Li, Kristen E DeMeester, Victor Cociorva, Mark A Herzik, F Ulrich Hartl, Bruno Melillo, Benjamin F Cravatt","doi":"10.1038/s41589-026-02348-1","DOIUrl":"10.1038/s41589-026-02348-1","url":null,"abstract":"Activity-based protein profiling has identified hundreds of human proteins from diverse classes that react at cysteine residues with stereochemically defined electrophilic compounds (stereoprobes). The structure-activity relationships underlying these stereoprobe-protein interactions, however, remain poorly understood. Here, we show that the protein interaction landscape of tryptoline acrylamide stereoprobes can be profoundly altered by structural modifications distal to the acrylamide reactive group. Most stereoprobe liganding events occurred at nonorthosteric sites and evaded assignment by the machine learning-based cofolding model Boltz-2, which instead tended to misplace stereoprobes in orthosteric pockets (an outcome we term 'orthostery burnout'). We found that stereoprobes reacting with C124 in the nucleotide exchange factor GRPEL1 disrupt interactions with the mitochondrial HSP70 chaperone HSPA9/mortalin, leading to impairments in mitochondrial protein import and mitophagy induction. Our results highlight tryptoline acrylamides as a versatile source of covalent ligands targeting nonorthosteric sites on proteins, including tool compounds that perturb the mitochondrial HSP70 chaperone system.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207355","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

Beyond the obvious pocket. 在明显的口袋之外。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-10-16 DOI: 10.1038/s41589-026-02326-7

Xinchao Shi, Jian Zhang

引用次数: 0

Single Staphylococcus aureus SauUSI restriction enzyme motors fragment methylated DNA. 单个金黄色葡萄球菌SauUSI限制性内切酶驱动片段甲基化DNA。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-10-15 DOI: 10.1038/s41589-026-02353-4

Steven J Shaw, Alex Hughes-Games, Oscar E Torres Montaguth, Sam McDowall, Fiona M Diffin, Daniel Dunn, Stephen J Cross, Mark D Szczelkun

{"title":"Single Staphylococcus aureus SauUSI restriction enzyme motors fragment methylated DNA.","authors":"Steven J Shaw, Alex Hughes-Games, Oscar E Torres Montaguth, Sam McDowall, Fiona M Diffin, Daniel Dunn, Stephen J Cross, Mark D Szczelkun","doi":"10.1038/s41589-026-02353-4","DOIUrl":"https://doi.org/10.1038/s41589-026-02353-4","url":null,"abstract":"SauUSI is a dimeric, ATP-dependent type IV restriction enzyme that protects Staphylococcus aureus by cleaving nonself DNA containing 5-methylcytosine or 5-hydroxymethylcytosine. Using biophysical, single-molecule and nanopore sequencing methods, we show that 5-methylcytosine recognition first induces ATP-driven unidirectional translocation by one helicase-like subunit, displacing its target recognition domain (TRD). In half of events, the partner TRD can then bind the liberated modified site, stabilizing a growing DNA loop. On symmetrically methylated DNA, looping is more frequent and both motors can engage in bidirectional loop translocation. Cleavage occurs stochastically throughout translocation but events that increase dwell time such as rebinding methylated sites elevate the chance of cleavage. Interactions with other SauUSI dimers or protein roadblocks influence cleavage distributions but are not required for nuclease activation. While the first cleavages principally generate 1-nt 3' overhangs or blunt ends, multiple binding-translocation-cleavage cycles by individual enzymes ultimately fragment the modified nonself DNA, neutralizing its threat.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195338","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

PRADA enables in vivo peroxidase proximity labeling for multiomics. PRADA使体内过氧化物酶接近标记为多组学。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-10-14 DOI: 10.1038/s41589-026-02351-6

引用次数: 0

Targeting ribosome biogenesis. 靶向核糖体生物发生。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-10-13 DOI: 10.1038/s41589-026-02344-5

Michael Prattes, Helmut Bergler

引用次数: 0

A selective NVL inhibitor suppresses tumor growth by targeting ribosome biogenesis. 选择性NVL抑制剂通过靶向核糖体生物发生抑制肿瘤生长。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-10-13 DOI: 10.1038/s41589-026-02324-9

Holly H Guo, Ye Tao, Victor E Cruz, Divya Reddy, Min Fang, Vishal Khivansara, Shanhai Xie, Ashley Leach, Johann Peterson, Garrett C Kimble, Michael Buszczak, Jiwoong Kim, Noelle S Williams, Arin B Aurora, Jan P Erzberger, Jef K De Brabander, Deepak Nijhawan

{"title":"A selective NVL inhibitor suppresses tumor growth by targeting ribosome biogenesis.","authors":"Holly H Guo, Ye Tao, Victor E Cruz, Divya Reddy, Min Fang, Vishal Khivansara, Shanhai Xie, Ashley Leach, Johann Peterson, Garrett C Kimble, Michael Buszczak, Jiwoong Kim, Noelle S Williams, Arin B Aurora, Jan P Erzberger, Jef K De Brabander, Deepak Nijhawan","doi":"10.1038/s41589-026-02324-9","DOIUrl":"10.1038/s41589-026-02324-9","url":null,"abstract":"Ribosome biogenesis is highly upregulated in cancer and essential for malignant growth, yet efforts to selectively target this process pharmacologically have been unsuccessful. Here we identify nuclear valosin-containing protein-like (NVL), a hexameric AAA+ ATPase required for large ribosomal subunit (60S) assembly, as a druggable target in this pathway. Using forward genetics, we discovered that the cytotoxic dibenzothiazepinone MM17 inhibits NVL. Mutations conferring resistance to MM17 in cancer cells also rendered recombinant NVL refractory to enzymatic inhibition in vitro, providing convergent genetic and biochemical evidence of target engagement. Cryo-electron microscopy structures revealed two MM17-binding sites within the NVL hexamer, with resistance mutations clustering around the ligand pocket. NVL inhibition disrupts 60S biogenesis and activates p53 without inducing DNA damage. A more potent, bioavailable analog, MM927, recapitulates these effects and suppresses tumor growth in vivo without detectable toxicity. These findings establish NVL inhibitors as first-in-class therapeutics targeting ribosome biogenesis in cancer.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183031","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

An RNA mark for pluripotency. 多能性的RNA标记。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-10-12 DOI: 10.1038/s41589-026-02337-4

Manish Kumar, Jing Liu

引用次数: 0

PUS7 pseudouridylation of 7SK orchestrates human somatic cell reprogramming into iPS cells. 7SK的PUS7假尿嘧啶化协调了人类体细胞重编程为iPS细胞。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-10-12 DOI: 10.1038/s41589-026-02339-2

Hongxia Cai, Cheng-Wei Ju, Jianfei Chao, Yunzheng Liu, Peng Ye, Xuanhao Zhu, Ruitu Lyu, Yutao Zhao, Chenyou Zhu, Yuxuan Li, Xiwei Wu, Arthur Li, Jiangbo Wei, Li-Sheng Zhang, Fowzan Sami Alkuraya, Arjan P M de Brouwer, Chuan He, Yanhong Shi

{"title":"PUS7 pseudouridylation of 7SK orchestrates human somatic cell reprogramming into iPS cells.","authors":"Hongxia Cai, Cheng-Wei Ju, Jianfei Chao, Yunzheng Liu, Peng Ye, Xuanhao Zhu, Ruitu Lyu, Yutao Zhao, Chenyou Zhu, Yuxuan Li, Xiwei Wu, Arthur Li, Jiangbo Wei, Li-Sheng Zhang, Fowzan Sami Alkuraya, Arjan P M de Brouwer, Chuan He, Yanhong Shi","doi":"10.1038/s41589-026-02339-2","DOIUrl":"https://doi.org/10.1038/s41589-026-02339-2","url":null,"abstract":"Reprogramming human somatic cells into induced pluripotent stem cells (iPS cells) provides huge potential for regenerative medicine but its molecular regulation remains incompletely understood. In this study, we identify PUS7 as an RNA modification checkpoint that promotes acquisition of pluripotency. PUS7 loss markedly impairs reprogramming, whereas its overexpression accelerates reprogramming efficiency and kinetics. Mechanistically, PUS7 pseudouridylates U250 of the chromatin-associated noncoding RNA 7SK, enhancing its interaction with the BRG/BRM-associated factor (BAF) complex. Loss of this modification disrupts 7SK-BAF association, reduces BAF chromatin occupancy and decreases global chromatin accessibility. We further establish PSKM (PUS7, SOX2, KLF4, MYC) reprogramming, which generates iPS cells with faithful imprinting, robust lineage potential and improved developmental fidelity. PSKM-iPS cells differentiate efficiently toward neural and hematopoietic lineages and undergo gastrulation-like morphogenesis. These findings link 7SK pseudouridylation to chromatin remodeling and establish PSKM as a framework for generating high-quality human iPS cells for modeling and regenerative medicine.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165768","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

Proteome-guided drug discovery maps and mitigates therapeutic degrader toxicity. 蛋白质组引导的药物发现地图和减轻治疗降解毒性。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-10-09 DOI: 10.1038/s41589-026-02347-2

Shaon Basu, Jason Shu Lim Yu, Jessica Bosak, Sharan K Bagal, Claire Crafter, Charlene Fallan, Oliver Lemke, Anja Freiwald, Matthew E H White, Spyros I Vernardis, Christoph B Messner, Chrysiis Michaloglou, Kenneth Pryde, Antonio Ramos-Montoya, Sophie Regan, Monica Rodrigo-Brenni, Sascha Roth, Camilla Ruffilli, Michael Mülleder, Kevin Moreau, Markus Ralser

{"title":"Proteome-guided drug discovery maps and mitigates therapeutic degrader toxicity.","authors":"Shaon Basu, Jason Shu Lim Yu, Jessica Bosak, Sharan K Bagal, Claire Crafter, Charlene Fallan, Oliver Lemke, Anja Freiwald, Matthew E H White, Spyros I Vernardis, Christoph B Messner, Chrysiis Michaloglou, Kenneth Pryde, Antonio Ramos-Montoya, Sophie Regan, Monica Rodrigo-Brenni, Sascha Roth, Camilla Ruffilli, Michael Mülleder, Kevin Moreau, Markus Ralser","doi":"10.1038/s41589-026-02347-2","DOIUrl":"https://doi.org/10.1038/s41589-026-02347-2","url":null,"abstract":"Heterobifunctional targeted degraders (HBDs) enable potent removal of protein targets but their clinical success can be hindered by de novo toxicity inherent to their bivalent chemistry. Here we introduce a drug discovery framework that exploits high-throughput proteomics to map and mitigate toxicity mechanisms of emerging drug modalities. Exposing androgen receptor (AR)-negative cells to a library of experimental AR-HBDs indicated for treatment-resistant prostate cancer linked widespread proteomic responses to hepatotoxicity of phthalimide degraders. Machine learning trained on proteomes mapped the primary toxicity mechanism to inhibition of electron transport chain complex I and identified safer analogs where a minor modification in the linker region mitigated off-target engagement. Proteome-optimized degraders displayed decreased hepatotoxicity, enhanced specificity and antitumor activity against treatment-resistant prostate cancer xenografts. Our findings establish a versatile framework for developing safer medicines and highlight the transformative potential of proteome-guided drug discovery.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148139","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