Nature chemical biology最新文献_第10页

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":"27 1","pages":""},"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":"66 1","pages":""},"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":"11 1","pages":""},"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

Metabolic determinants of germinal center B cell formation and responses 生殖中心 B 细胞形成和反应的代谢决定因素

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-26 DOI: 10.1038/s41589-024-01690-6

Jun Wu, Jiawen Zhou, Gen Li, Xuan Sun, Chen Xiang, Haiyan Chen, Peng Jiang

{"title":"Metabolic determinants of germinal center B cell formation and responses","authors":"Jun Wu, Jiawen Zhou, Gen Li, Xuan Sun, Chen Xiang, Haiyan Chen, Peng Jiang","doi":"10.1038/s41589-024-01690-6","DOIUrl":"https://doi.org/10.1038/s41589-024-01690-6","url":null,"abstract":"Germinal center (GC) B cells are crucial for the generation of GCs and long-lived humoral immunity. Here we report that one-carbon metabolism determines the formation and responses of GC B cells. Upon CD40 stimulation, GC B cells selectively upregulate methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression to generate purines and the antioxidant glutathione. MTHFD2 depletion reduces GC B cell frequency and antigen-specific antibody production. Moreover, supplementation with nucleotides and antioxidants suffices to promote GC B cell formation and function in vitro and in vivo through activation of the mammalian target of rapamycin complex 1 signaling pathway. Moreover, we found that antigen stimulation enhances YY1 binding to the Mthfd2 promoter and promotes MTHFD2 transcription. Interestingly, these findings can be generalized to the pentose phosphate pathway, which is another major source of reducing power and nucleotides. Therefore, these results suggest that an increased capacity for nucleotide synthesis and redox balance is required for GC B cell formation and responses, revealing a key aspect of GC B cell fate determination.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"9 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764443","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

Splice-modifying drug mechanisms 改变拼接的药物机制

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-26 DOI: 10.1038/s41589-024-01678-2

Jorge Herrero-Vicente, Douglas L. Black, Juan Valcárcel

引用次数: 0

Genetically engineered synthetic cells activate cargo release upon temperature shift 基因工程合成细胞在温度变化时激活货物释放。

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-07-25 DOI: 10.1038/s41589-024-01701-6

引用次数: 0

Unlocking saponin biosynthesis in soapwort 揭开肥皂草中皂甙生物合成的神秘面纱

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-23 DOI: 10.1038/s41589-024-01681-7

Seohyun Jo, Amr El-Demerdash, Charlotte Owen, Vikas Srivastava, Dewei Wu, Shingo Kikuchi, James Reed, Hannah Hodgson, Alex Harkess, Shengqiang Shu, Chris Plott, Jerry Jenkins, Melissa Williams, Lori-Beth Boston, Elia Lacchini, Tongtong Qu, Alain Goossens, Jane Grimwood, Jeremy Schmutz, Jim Leebens-Mack, Anne Osbourn

{"title":"Unlocking saponin biosynthesis in soapwort","authors":"Seohyun Jo, Amr El-Demerdash, Charlotte Owen, Vikas Srivastava, Dewei Wu, Shingo Kikuchi, James Reed, Hannah Hodgson, Alex Harkess, Shengqiang Shu, Chris Plott, Jerry Jenkins, Melissa Williams, Lori-Beth Boston, Elia Lacchini, Tongtong Qu, Alain Goossens, Jane Grimwood, Jeremy Schmutz, Jim Leebens-Mack, Anne Osbourn","doi":"10.1038/s41589-024-01681-7","DOIUrl":"https://doi.org/10.1038/s41589-024-01681-7","url":null,"abstract":"Soapwort (Saponaria officinalis) is a flowering plant from the Caryophyllaceae family with a long history of human use as a traditional source of soap. Its detergent properties are because of the production of polar compounds (saponins), of which the oleanane-based triterpenoid saponins, saponariosides A and B, are the major components. Soapwort saponins have anticancer properties and are also of interest as endosomal escape enhancers for targeted tumor therapies. Intriguingly, these saponins share common structural features with the vaccine adjuvant QS-21 and, thus, represent a potential alternative supply of saponin adjuvant precursors. Here, we sequence the S. officinalis genome and, through genome mining and combinatorial expression, identify 14 enzymes that complete the biosynthetic pathway to saponarioside B. These enzymes include a noncanonical cytosolic GH1 (glycoside hydrolase family 1) transglycosidase required for the addition of d-quinovose. Our results open avenues for accessing and engineering natural and new-to-nature pharmaceuticals, drug delivery agents and potential immunostimulants.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"65 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750316","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

Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms 大环内酯类药物以细菌核糖体和 DNA 回旋酶为靶标，可规避抗药性机制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-07-22 DOI: 10.1038/s41589-024-01685-3

Elena V. Aleksandrova, Cong-Xuan Ma, Dorota Klepacki, Faezeh Alizadeh, Nora Vázquez-Laslop, Jian-Hua Liang, Yury S. Polikanov, Alexander S. Mankin

{"title":"Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms","authors":"Elena V. Aleksandrova, Cong-Xuan Ma, Dorota Klepacki, Faezeh Alizadeh, Nora Vázquez-Laslop, Jian-Hua Liang, Yury S. Polikanov, Alexander S. Mankin","doi":"10.1038/s41589-024-01685-3","DOIUrl":"https://doi.org/10.1038/s41589-024-01685-3","url":null,"abstract":"Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"76 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141737004","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