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Guiding generative AI
IF 12.9 1区 生物学
Nature chemical biology Pub Date : 2025-02-25 DOI: 10.1038/s41589-025-01854-y
Russell Johnson
{"title":"Guiding generative AI","authors":"Russell Johnson","doi":"10.1038/s41589-025-01854-y","DOIUrl":"10.1038/s41589-025-01854-y","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 3","pages":"311-311"},"PeriodicalIF":12.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485667","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
Turning down the heat
IF 12.9 1区 生物学
Nature chemical biology Pub Date : 2025-02-25 DOI: 10.1038/s41589-025-01855-x
Grant Miura
{"title":"Turning down the heat","authors":"Grant Miura","doi":"10.1038/s41589-025-01855-x","DOIUrl":"10.1038/s41589-025-01855-x","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 3","pages":"311-311"},"PeriodicalIF":12.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485668","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 molecules deliver big
IF 12.9 1区 生物学
Nature chemical biology Pub Date : 2025-02-25 DOI: 10.1038/s41589-025-01856-w
Gene Chong
{"title":"Small molecules deliver big","authors":"Gene Chong","doi":"10.1038/s41589-025-01856-w","DOIUrl":"10.1038/s41589-025-01856-w","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 3","pages":"311-311"},"PeriodicalIF":12.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485671","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
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":"<p>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.</p><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
{"title":"Tracking E2-specific substrates","authors":"Hannah B. L. Jones, Andreas Damianou, Benedikt M. Kessler","doi":"10.1038/s41589-025-01848-w","DOIUrl":"https://doi.org/10.1038/s41589-025-01848-w","url":null,"abstract":"Advanced E2-modified ubiquitin probes enable investigation of E2-selective ubiquitination in cells and the discovery of tyrosine ubiquitination as a modification occurring in a UBE2D3-specific manner.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"175 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443715","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
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
{"title":"The small molecule Ebio3 inactivates the KCNQ2 channel without blocking the pore","authors":"","doi":"10.1038/s41589-025-01853-z","DOIUrl":"https://doi.org/10.1038/s41589-025-01853-z","url":null,"abstract":"The small molecule Ebio3 inactivates the ‘non-inactivating’ potassium channel KCNQ2. This inhibition occurs by a unique ‘squeeze-to-inhibit’ mechanism, rather than by blocking the channel pore as most KCNQ2 inhibitors do, offering a new mechanism for modulating voltage-gated ion channels with implications for drug discovery.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"13 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443707","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
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
{"title":"xrRNAs adopt a long-lived conformation that prevents exonuclease activity","authors":"","doi":"10.1038/s41589-025-01844-0","DOIUrl":"https://doi.org/10.1038/s41589-025-01844-0","url":null,"abstract":"Biomolecules morph between conformations with distinct lifetimes according to their functional requirements. Mosquito-borne flaviviruses encode exoribonuclease-resistant RNAs (xrRNAs) that fold into knot-like structures to prevent exonuclease Xrn1 digestion. To achieve high Xrn1 resistance, xrRNAs contain molecular interactions with lifetimes that persist up to ten million times longer than canonical base pairs.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"326 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443714","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
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
{"title":"Visualizing drug effects over time in live animals using optical pharmacodynamics","authors":"","doi":"10.1038/s41589-025-01847-x","DOIUrl":"https://doi.org/10.1038/s41589-025-01847-x","url":null,"abstract":"Measuring pharmacodynamics is crucial for drug development, but traditional pharmacodynamic studies based on tissue dissection and subsequent biochemical analysis are labor- and resource-intensive. We developed a non-invasive imaging method to efficiently and rapidly visualize the pharmacodynamics of kinase inhibitors and degraders using an engineered kinase-modulated bioluminescent indicator.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"23 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418041","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
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":"<p>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 ~10<sup>5</sup>–10<sup>7</sup> 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.</p><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":"<p>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.</p><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
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