Nature chemical biology最新文献_第4页

Pharmacodynamics of Akt drugs revealed by a kinase-modulated bioluminescent indicator

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-02-11 DOI: 10.1038/s41589-025-01846-y

Yan Wu, Chenzhou Hao, Chao Gao, Matt Hageman, Sungmoo Lee, Thomas A. Kirkland, Nathanael S. Gray, Yichi Su, Michael Z. Lin

{"title":"Pharmacodynamics of Akt drugs revealed by a kinase-modulated bioluminescent indicator","authors":"Yan Wu, Chenzhou Hao, Chao Gao, Matt Hageman, Sungmoo Lee, Thomas A. Kirkland, Nathanael S. Gray, Yichi Su, Michael Z. Lin","doi":"10.1038/s41589-025-01846-y","DOIUrl":"https://doi.org/10.1038/s41589-025-01846-y","url":null,"abstract":"Measuring pharmacodynamics (PD)—the biochemical effects of drug dosing—and correlating them with therapeutic efficacy in animal models is crucial for the development of effective drugs but traditional PD studies are labor and resource intensive. Here we developed a kinase-modulated bioluminescent indicator (KiMBI) for rapid, noninvasive PD assessment of Akt-targeted drugs, minimizing drug and animal use. Using KiMBI, we performed a structure–PD relationship analysis on the brain-active Akt inhibitor ipatasertib by generating and characterizing two novel analogs. One analog, ML-B01, successfully inhibited Akt in both the brain and the body. Interestingly, capivasertib, ipatasertib and ML-B01 all exhibited PD durations beyond their pharmacokinetic profiles. Furthermore, KiMBI revealed that the PD effects of an Akt-targeted proteolysis-targeting chimera degrader endured for over 3 days. Thus, bioluminescence imaging with Akt KiMBI provides a noninvasive and efficient method for in vivo visualization of the PD of Akt inhibitors and degraders.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"26 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143384994","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

Expanding the molecular grammar of polar residues and arginine in FUS phase separation

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-02-07 DOI: 10.1038/s41589-024-01828-6

Noah Wake, Shuo-Lin Weng, Tongyin Zheng, Szu-Huan Wang, Valentin Kirilenko, Jeetain Mittal, Nicolas L. Fawzi

{"title":"Expanding the molecular grammar of polar residues and arginine in FUS phase separation","authors":"Noah Wake, Shuo-Lin Weng, Tongyin Zheng, Szu-Huan Wang, Valentin Kirilenko, Jeetain Mittal, Nicolas L. Fawzi","doi":"10.1038/s41589-024-01828-6","DOIUrl":"https://doi.org/10.1038/s41589-024-01828-6","url":null,"abstract":"A molecular grammar governing low-complexity prion-like domain phase separation (PS) has identified tyrosine and arginine as primary drivers via aromatic–aromatic and aromatic–arginine interactions. Here we show that additional residues and contacts contribute to PS, highlighting the need to include these contributions in PS theories and models. Tyrosine and arginine make important contacts beyond tyrosine–tyrosine and tyrosine–arginine, including arginine–arginine contacts. Among polar residues, glutamine contributes to PS with sequence and position specificity, contacting tyrosine, arginine and other residues, both before PS and in condensed phases. The flexibility of glycine enhances PS by allowing favorable contacts between adjacent residues and inhibits the liquid-to-solid transition. Polar residues also make sequence-specific contributions to liquid-to-solid transition, with serine positions linked to the formation of an amyloid-core structure by the FUS low-complexity domain. Hence, an extended molecular grammar expands the role of arginine and polar residues in prion-like domain protein PS and reveals the position dependence of residue contribution to solidification.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"26 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258216","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

Persistent activation of TRPM4 triggers necrotic cell death characterized by sodium overload

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-02-06 DOI: 10.1038/s41589-025-01841-3

Wan Fu, Jianghuang Wang, Tianyu Li, Yuhui Qiao, Zili Zhang, Xiaomin Zhang, Mingkai He, Yan Su, Ziye Zhao, Chen Li, Ronghua Xiao, Yujun Han, Shen Zhang, Zhiqiang Liu, James Lin, Guoqiang Chen, Yang Li, Qing Zhong

{"title":"Persistent activation of TRPM4 triggers necrotic cell death characterized by sodium overload","authors":"Wan Fu, Jianghuang Wang, Tianyu Li, Yuhui Qiao, Zili Zhang, Xiaomin Zhang, Mingkai He, Yan Su, Ziye Zhao, Chen Li, Ronghua Xiao, Yujun Han, Shen Zhang, Zhiqiang Liu, James Lin, Guoqiang Chen, Yang Li, Qing Zhong","doi":"10.1038/s41589-025-01841-3","DOIUrl":"https://doi.org/10.1038/s41589-025-01841-3","url":null,"abstract":"Sodium influx and overload are frequently observed in human tissue injuries. Whether sodium overload imposes a causative effect on necrotic cell death and the mechanism involved are unclear. Here we identify necrocide 1 (NC1) as a compound that induces necrotic cell death through sodium overload, termed NECSO for necrosis by sodium overload. NC1 targets the transient receptor potential cation channel subfamily M member 4 (TRPM4), a nonselective monovalent cation channel, to promote Na+ influx and necrosis. TRPM4-deficient cells are resistant to NC1-induced NECSO. NC1 specifically activates human TRPM4, not mouse TRPM4, because of differences in a transmembrane region, as revealed by domain swapping and molecular docking. Gain-of-function mutations in human TRPM4 linked to cardiac arrhythmias show increased vulnerability to NECSO triggered by NC1 or 2-deoxy-d-glucose. Chemical screening identified NECSO inhibitors that block necrosis induced by NC1 or energy depletion. These findings provide insights into regulated Na+ influx-mediated necrosis and its implications for disease.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"85 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192012","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

Programming biological communication between distinct membraneless compartments 在不同的无膜区之间编程进行生物交流

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-02-05 DOI: 10.1038/s41589-025-01840-4

Bo-Tao Ji, He-Tong Pan, Zhi-Gang Qian, Xiao-Xia Xia

引用次数: 0

REPLACE-ing RNA through evolution

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-02-04 DOI: 10.1038/s41589-025-01845-z

Christopher E. Denes, G. Gregory Neely

引用次数: 0

ADSL promotes autophagy and tumor growth through fumarate-mediated Beclin1 dimethylation

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-29 DOI: 10.1038/s41589-024-01825-9

Lei Wang, Runze Shi, Shuo Wang, Yuran Duan, Zheng Wang, Peixiang Zheng, Xue Sun, Xiaohan Chen, Guimei Ji, Yuli Shen, Bofei Dong, Yanni Lin, Ting Wen, Qi Tian, Zhanpeng Guo, Yueru Hou, Shiqi Wu, Ling Xiao, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Sofie Duan, Xueli Bai, Tong Liu, Zhiren Zhang, Peng Zhan, Zhimin Lu, Daqian Xu

{"title":"ADSL promotes autophagy and tumor growth through fumarate-mediated Beclin1 dimethylation","authors":"Lei Wang, Runze Shi, Shuo Wang, Yuran Duan, Zheng Wang, Peixiang Zheng, Xue Sun, Xiaohan Chen, Guimei Ji, Yuli Shen, Bofei Dong, Yanni Lin, Ting Wen, Qi Tian, Zhanpeng Guo, Yueru Hou, Shiqi Wu, Ling Xiao, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Sofie Duan, Xueli Bai, Tong Liu, Zhiren Zhang, Peng Zhan, Zhimin Lu, Daqian Xu","doi":"10.1038/s41589-024-01825-9","DOIUrl":"https://doi.org/10.1038/s41589-024-01825-9","url":null,"abstract":"As an enzyme with a critical role in de novo purine synthesis, adenylosuccinate lyase (ADSL) expression is upregulated in various malignancies. However, whether ADSL possesses noncanonical functions that contribute to cancer progression remains poorly understood. Here, we demonstrate that protein kinase R-like endoplasmic reticulum kinase (PERK) activated by lipid deprivation or ER stress phosphorylates ADSL at S140, leading to an enhanced association between ADSL and Beclin1. Beclin1-associated ADSL produces fumarate, which in turn inhibits lysine demethylase 8-mediated Beclin1 demethylation, resulting in enhanced Beclin1 K117me2, subsequent disruption of the binding of BCL-2 to Beclin1 and elevated autophagy. Blocking the ADSL–Beclin1 axis by knock-in mutation or a cell-penetrating peptide inhibits autophagy induced by lipid deprivation and ER stress and blunts liver tumor growth in mice. Additionally, ADSL pS140-upregulated Beclin1 K117me2 levels are positively correlated with autophagy levels in human hepatocellular carcinoma specimens and poor patient prognosis. These findings uncover the function of ADSL in autophagy regulation and liver tumor development.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"7 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055014","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

Quinone extraction drives atmospheric carbon monoxide oxidation in bacteria

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-29 DOI: 10.1038/s41589-025-01836-0

Ashleigh Kropp, David L. Gillett, Hari Venugopal, Miguel A. Gonzálvez, James P. Lingford, Surbhi Jain, Christopher K. Barlow, Jie Zhang, Chris Greening, Rhys Grinter

{"title":"Quinone extraction drives atmospheric carbon monoxide oxidation in bacteria","authors":"Ashleigh Kropp, David L. Gillett, Hari Venugopal, Miguel A. Gonzálvez, James P. Lingford, Surbhi Jain, Christopher K. Barlow, Jie Zhang, Chris Greening, Rhys Grinter","doi":"10.1038/s41589-025-01836-0","DOIUrl":"https://doi.org/10.1038/s41589-025-01836-0","url":null,"abstract":"Diverse bacteria and archaea use atmospheric CO as an energy source for long-term survival. Bacteria use [MoCu]-CO dehydrogenases (Mo-CODH) to convert atmospheric CO to carbon dioxide, transferring the obtained electrons to the aerobic respiratory chain. However, it is unknown how these enzymes oxidize CO at low concentrations and interact with the respiratory chain. Here, we use cryo-electron microscopy and structural modeling to show how Mo-CODHMs (CoxSML) from Mycobacterium smegmatis interacts with its partner, the membrane-bound menaquinone-binding protein CoxG. We provide electrochemical, biochemical and genetic evidence that Mo-CODH transfers CO-derived electrons to the aerobic respiratory chain through CoxG. Lastly, we show that Mo-CODH and CoxG genetically and structurally associate in diverse bacteria and archaea. These findings reveal the basis of the biogeochemically and ecologically important process of atmospheric CO oxidation, while demonstrating that long-range quinone transport is a general mechanism of energy conservation, which convergently evolved on multiple occasions.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"52 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054911","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

Mechanistic insights and approaches for beta cell regeneration

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-29 DOI: 10.1038/s41589-024-01822-y

Christos Karampelias, Ka-Cheuk Liu, Anders Tengholm, Olov Andersson

{"title":"Mechanistic insights and approaches for beta cell regeneration","authors":"Christos Karampelias, Ka-Cheuk Liu, Anders Tengholm, Olov Andersson","doi":"10.1038/s41589-024-01822-y","DOIUrl":"https://doi.org/10.1038/s41589-024-01822-y","url":null,"abstract":"Diabetes is characterized by variable loss of insulin-producing beta cells, and new regenerative approaches to increasing the functional beta cell mass of patients hold promise for reversing disease progression. In this Review, we summarize recent chemical biology breakthroughs advancing our knowledge of beta cell regeneration. We present current chemical-based tools, sensors and mechanistic insights into pathways that can be targeted to enhance beta cell regeneration in model organisms. We group the pathways according to the cellular processes they affect, that is, proliferation, conversion of other mature cell types to beta cells and beta cell differentiation from progenitor-like populations. We also suggest assays for assessing the functionality of the regenerated beta cells. Although regeneration processes differ between animal models, such as zebrafish, mice and pigs, regenerative mechanisms identified in any one animal model may be translatable to humans. Overall, chemical biology-based approaches in beta cell regeneration give hope that specific molecular pathways can be targeted to enhance beta cell regeneration.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"9 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055013","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

How to build a [2Fe–2S] cluster 如何构建 [2Fe-2S] 簇

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-28 DOI: 10.1038/s41589-024-01835-7

Anna Moseler, Stephan Wagner, Andreas J. Meyer

引用次数: 0

The measurement, regulation and biological activity of FAHFAs

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-28 DOI: 10.1038/s41589-024-01827-7

Dan Tan, Alan Saghatelian

引用次数: 0