Nature chemical biology最新文献

Quantitative chemoproteomics reveals dopamine’s protective modification of Tau

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-02-20 DOI: 10.1038/s41589-025-01849-9

Qianwen Wang, Zhengtao Liu, Youjia Wang, Yuan Liu, Ying Chen, Shengnan Zhang, Wen Zeng, Dan Li, Fan Yang, Zhuohao He, Weidi Xiao, Cong Liu, Chu Wang

{"title":"Quantitative chemoproteomics reveals dopamine’s protective modification of Tau","authors":"Qianwen Wang, Zhengtao Liu, Youjia Wang, Yuan Liu, Ying Chen, Shengnan Zhang, Wen Zeng, Dan Li, Fan Yang, Zhuohao He, Weidi Xiao, Cong Liu, Chu Wang","doi":"10.1038/s41589-025-01849-9","DOIUrl":"https://doi.org/10.1038/s41589-025-01849-9","url":null,"abstract":"Dopamine (DA) is one of the most important neurotransmitters. Its oxidation leads to electrophilic quinone, which covalently modifies nucleophilic residues in proteins, resulting in ‘dopamination’. Individual dopaminated proteins have been studied, most of which were functionally damaged by dopamination. Here, we developed a quantitative chemoproteomic strategy to site-specifically measure proteins’ dopamination. More than 6,000 dopamination sites were quantified. Half-maximal inhibitory concentration values for 63 hypersensitive sites were measured. Among them, hypersensitive dopamination of two cysteines in microtubule-associated protein Tau was biochemically validated and functionally characterized to prevent Tau’s amyloid fibrillation and promote Tau-mediated assembly of microtubules. In addition, endogenous dopamination of Tau in mouse brain was detected through targeted mass spectrometry analysis. Our study not only provides a global portrait of dopamination but also discovers a protective role of DA in regulating the function of Tau, which will enhance our understanding of the physiological and pathological functions of DA in human brain.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"25 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452024","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

Tracking E2-specific substrates

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-02-19 DOI: 10.1038/s41589-025-01848-w

Hannah B. L. Jones, Andreas Damianou, Benedikt M. Kessler

引用次数: 0

The small molecule Ebio3 inactivates the KCNQ2 channel without blocking the pore

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-02-19 DOI: 10.1038/s41589-025-01853-z

引用次数: 0

xrRNAs adopt a long-lived conformation that prevents exonuclease activity

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-02-19 DOI: 10.1038/s41589-025-01844-0

引用次数: 0

Visualizing drug effects over time in live animals using optical pharmacodynamics

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-02-14 DOI: 10.1038/s41589-025-01847-x

引用次数: 0

Lifetime of ground conformational state determines the activity of structured RNA

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-02-12 DOI: 10.1038/s41589-025-01843-1

Rhese D. Thompson, Derek L. Carbaugh, Joshua R. Nielsen, Ciara M. Witt, Edgar M. Faison, Rita M. Meganck, Atul Rangadurai, Bo Zhao, Jeffrey P. Bonin, Nathan I. Nicely, William F. Marzluff, Aaron T. Frank, Helen M. Lazear, Qi Zhang

{"title":"Lifetime of ground conformational state determines the activity of structured RNA","authors":"Rhese D. Thompson, Derek L. Carbaugh, Joshua R. Nielsen, Ciara M. Witt, Edgar M. Faison, Rita M. Meganck, Atul Rangadurai, Bo Zhao, Jeffrey P. Bonin, Nathan I. Nicely, William F. Marzluff, Aaron T. Frank, Helen M. Lazear, Qi Zhang","doi":"10.1038/s41589-025-01843-1","DOIUrl":"https://doi.org/10.1038/s41589-025-01843-1","url":null,"abstract":"Biomolecules continually sample alternative conformations. Consequently, even the most energetically favored ground conformational state has a finite lifetime. Here, we show that, in addition to the three-dimensional (3D) structure, the lifetime of a ground conformational state determines its biological activity. Using hydrogen–deuterium exchange nuclear magnetic resonance spectroscopy, we found that Zika virus exoribonuclease-resistant RNA (xrRNA) encodes a ground conformational state with a lifetime that is ~105–107 longer than that of canonical base pairs. Mutations that shorten the apparent lifetime of the ground state without affecting its 3D structure decreased exoribonuclease resistance in vitro and impaired virus replication in cells. Additionally, we observed this exceptionally long-lived ground state in xrRNAs from diverse infectious mosquito-borne flaviviruses. These results demonstrate the biological importance of the lifetime of a preorganized ground state and further suggest that elucidating the lifetimes of dominant 3D structures of biomolecules may be crucial for understanding their behaviors and functions.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"16 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393097","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

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