Nature chemical biology最新文献_第9页

Solving the mystery of enediyne biosynthesis 解开烯二炔生物合成之谜

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-30 DOI: 10.1038/s41589-024-01686-2

Max B. Sosa, Michelle C. Y. Chang

引用次数: 0

Under pressure 在压力下

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-29 DOI: 10.1038/s41589-024-01696-0

Gene Chong

引用次数: 0

RNA-guided recombination RNA 引导的重组

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-29 DOI: 10.1038/s41589-024-01697-z

Yiyun Song

引用次数: 0

A place to dock 停靠的地方

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-29 DOI: 10.1038/s41589-024-01695-1

Grant Miura

引用次数: 0

CRISPR-repressed toxin–antitoxin provides herd immunity against anti-CRISPR elements CRISPR抑制毒素-抗毒素可提供针对抗CRISPR元件的群体免疫力

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-29 DOI: 10.1038/s41589-024-01693-3

Xian Shu, Rui Wang, Zhihua Li, Qiong Xue, Jiajun Wang, Jingfang Liu, Feiyue Cheng, Chao Liu, Huiwei Zhao, Chunyi Hu, Jie Li, Songying Ouyang, Ming Li

{"title":"CRISPR-repressed toxin–antitoxin provides herd immunity against anti-CRISPR elements","authors":"Xian Shu, Rui Wang, Zhihua Li, Qiong Xue, Jiajun Wang, Jingfang Liu, Feiyue Cheng, Chao Liu, Huiwei Zhao, Chunyi Hu, Jie Li, Songying Ouyang, Ming Li","doi":"10.1038/s41589-024-01693-3","DOIUrl":"https://doi.org/10.1038/s41589-024-01693-3","url":null,"abstract":"Prokaryotic clustered regularly interspaced short palindromic repeat (CRISPR)–Cas systems are highly vulnerable to phage-encoded anti-CRISPR (Acr) factors. How CRISPR–Cas systems protect themselves remains unclear. Here we uncovered a broad-spectrum anti-anti-CRISPR strategy involving a phage-derived toxic protein. Transcription of this toxin is normally repressed by the CRISPR–Cas effector but is activated to halt cell division when the effector is inhibited by any anti-CRISPR proteins or RNAs. We showed that this abortive infection-like effect efficiently expels Acr elements from bacterial population. Furthermore, we exploited this anti-anti-CRISPR mechanism to develop a screening method for specific Acr candidates for a CRISPR–Cas system and successfully identified two distinct Acr proteins that enhance the binding of CRISPR effector to nontarget DNA. Our data highlight the broad-spectrum role of CRISPR-repressed toxins in counteracting various types of Acr factors. We propose that the regulatory function of CRISPR–Cas confers host cells herd immunity against Acr-encoding genetic invaders whether they are CRISPR targeted or not.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790965","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

Making transient complexes stick 让瞬态复合体持久

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-29 DOI: 10.1038/s41589-024-01649-7

YiYu Wang, M. S. S. Vinod Mouli, Min Ma, Fleur M. Ferguson

引用次数: 0

Template-assisted covalent modification underlies activity of covalent molecular glues 模板辅助共价修饰是共价分子胶活性的基础

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-29 DOI: 10.1038/s41589-024-01668-4

Yen-Der Li, Michelle W. Ma, Muhammad Murtaza Hassan, Moritz Hunkeler, Mingxing Teng, Kedar Puvar, Justine C. Rutter, Ryan J. Lumpkin, Brittany Sandoval, Cyrus Y. Jin, Anna M. Schmoker, Scott B. Ficarro, Hakyung Cheong, Rebecca J. Metivier, Michelle Y. Wang, Shawn Xu, Woong Sub Byun, Brian J. Groendyke, Inchul You, Logan H. Sigua, Isidoro Tavares, Charles Zou, Jonathan M. Tsai, Paul M. C. Park, Hojong Yoon, Felix C. Majewski, Haniya T. Sperling, Jarrod A. Marto, Jun Qi, Radosław P. Nowak, Katherine A. Donovan, Mikołaj Słabicki, Nathanael S. Gray, Eric S. Fischer, Benjamin L. Ebert

{"title":"Template-assisted covalent modification underlies activity of covalent molecular glues","authors":"Yen-Der Li, Michelle W. Ma, Muhammad Murtaza Hassan, Moritz Hunkeler, Mingxing Teng, Kedar Puvar, Justine C. Rutter, Ryan J. Lumpkin, Brittany Sandoval, Cyrus Y. Jin, Anna M. Schmoker, Scott B. Ficarro, Hakyung Cheong, Rebecca J. Metivier, Michelle Y. Wang, Shawn Xu, Woong Sub Byun, Brian J. Groendyke, Inchul You, Logan H. Sigua, Isidoro Tavares, Charles Zou, Jonathan M. Tsai, Paul M. C. Park, Hojong Yoon, Felix C. Majewski, Haniya T. Sperling, Jarrod A. Marto, Jun Qi, Radosław P. Nowak, Katherine A. Donovan, Mikołaj Słabicki, Nathanael S. Gray, Eric S. Fischer, Benjamin L. Ebert","doi":"10.1038/s41589-024-01668-4","DOIUrl":"https://doi.org/10.1038/s41589-024-01668-4","url":null,"abstract":"Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed ‘template-assisted covalent modification’. We identified a new series of BRD4 molecular glue degraders that recruit CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58. This process stabilizes the formation of BRD4–degrader–DCAF16 ternary complex and facilitates BRD4 degradation. Supporting generalizability, we found that a subset of degraders also induces GAK–BRD4BD2 interaction through trans-labeling of GAK. Together, our work establishes ‘template-assisted covalent modification’ as a mechanism for covalent molecular glues, which opens a new path to proximity-driven pharmacology.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790966","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

Direct RAS inhibitors turn 10 直接 RAS 抑制剂变成 10

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-26 DOI: 10.1038/s41589-024-01691-5

Jonathan M. L. Ostrem, Ulf Peters, Kevan M. Shokat

引用次数: 0

Restoring susceptibility to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus 恢复耐甲氧西林金黄色葡萄球菌对β-内酰胺类抗生素的敏感性

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-26 DOI: 10.1038/s41589-024-01688-0

Van T. Nguyen, Biruk T. Birhanu, Vega Miguel-Ruano, Choon Kim, Mayte Batuecas, Jingdong Yang, Amr M. El-Araby, Eva Jiménez-Faraco, Valerie A. Schroeder, Alejandra Alba, Neha Rana, Safaa Sader, Caitlyn A. Thomas, Rhona Feltzer, Mijoon Lee, Jed F. Fisher, Juan A. Hermoso, Mayland Chang, Shahriar Mobashery

{"title":"Restoring susceptibility to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus","authors":"Van T. Nguyen, Biruk T. Birhanu, Vega Miguel-Ruano, Choon Kim, Mayte Batuecas, Jingdong Yang, Amr M. El-Araby, Eva Jiménez-Faraco, Valerie A. Schroeder, Alejandra Alba, Neha Rana, Safaa Sader, Caitlyn A. Thomas, Rhona Feltzer, Mijoon Lee, Jed F. Fisher, Juan A. Hermoso, Mayland Chang, Shahriar Mobashery","doi":"10.1038/s41589-024-01688-0","DOIUrl":"https://doi.org/10.1038/s41589-024-01688-0","url":null,"abstract":"Infections by Staphylococcus aureus have been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureus by acquisition of the bla and mec operons. The presence of the β-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4 is covalently engaged with the active-site serine of BlaR. Compound 4 potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureus strains. The combination of 4 with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764400","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

Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity 磷脂生物合成调节核苷酸代谢和还原能力

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-26 DOI: 10.1038/s41589-024-01689-z

Yibing Zhu, Xiaomeng Tong, Jingyuan Xue, Hong Qiu, Dan Zhang, Dao-Qiong Zheng, Zong-Cai Tu, Cunqi Ye

{"title":"Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity","authors":"Yibing Zhu, Xiaomeng Tong, Jingyuan Xue, Hong Qiu, Dan Zhang, Dao-Qiong Zheng, Zong-Cai Tu, Cunqi Ye","doi":"10.1038/s41589-024-01689-z","DOIUrl":"https://doi.org/10.1038/s41589-024-01689-z","url":null,"abstract":"Phospholipid and nucleotide syntheses are fundamental metabolic processes in eukaryotic organisms, with their dysregulation implicated in various disease states. Despite their importance, the interplay between these pathways remains poorly understood. Using genetic and metabolic analyses in Saccharomyces cerevisiae, we elucidate how cytidine triphosphate usage in the Kennedy pathway for phospholipid synthesis influences nucleotide metabolism and redox balance. We find that deficiencies in the Kennedy pathway limit nucleotide salvage, prompting compensatory activation of de novo nucleotide synthesis and the pentose phosphate pathway. This metabolic shift enhances the production of antioxidants such as NADPH and glutathione. Moreover, we observe that the Kennedy pathway for phospholipid synthesis is inhibited during replicative aging, indicating its role in antioxidative defense as an adaptive mechanism in aged cells. Our findings highlight the critical role of phospholipid synthesis pathway choice in the integrative regulation of nucleotide metabolism, redox balance and membrane properties for cellular defense.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764415","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