ACS Chemical Biology最新文献_第6页

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-07-18

Farah Kabir, Toshiaki Sonobe, Qian Zhu, Nandini Vallavoju, Yuka Amako and Christina M. Woo*,

引用次数: 0

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-07-18

Lior Soday, Chotima Seripracharat, Janine L. Gray, André F. S. Luz, Ryan T. Howard, Ravi Singh, Thomas J. Burden, Erika Bernardini, Miguel Mateus-Pinheiro, Jens Petersen, Anders Gunnarsson, Jenny Gunnarsson, Anna Aagaard, Tove Sjögren, Sarah Maslen, Edward J. Bartlett, Abigail F. Iles, David M. Smith, James S. Scott, Mark Skehel, Andrew M. Davis, Ana S. Ressurreição, Rui Moreira, Cecília M. P. Rodrigues, Avinash R. Shenoy and Edward W. Tate*,

引用次数: 0

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-07-18

Guoliang Zhu, Weize Yuan, Kun Wang, Huimin Wu, Kangjie Lv, Xinye Wang, Alex Tuffour, Biao Ren, Jingyu Zhang, Chenglin Jiang, Yi Jiang, Tom Hsiang, Peter Shen Yu, Frederick M Ausubel, Lixin Zhang, Huanqin Dai* and Xueting Liu*,

引用次数: 0

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-07-18

Jieyu Wang, Jialong Peng, Ming Cai, Yangbing Li, Fang He*, Hong-Hui Wang* and Zhou Nie*,

引用次数: 0

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-07-18

Tongyang Xu, Bowen Ma, Yuanpei Li, Zhihao Guo, Miaomiao Zhang and Billy Wai-Lung Ng*,

引用次数: 0

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-07-18

Shaimaa Tarek, Yasmin ElMaghloob, Hong Smith, Thomas J. Smith*, Marwa T. ElRakaiby* and Mohamed H. Habib*,

引用次数: 0

Discovery and Validation of a Novel Class of Necroptosis Inhibitors Targeting RIPK1. 一类新的靶向RIPK1的坏死性下垂抑制剂的发现和验证。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-07-18 Epub Date: 2025-06-20 DOI: 10.1021/acschembio.5c00112

Lior Soday, Chotima Seripracharat, Janine L Gray, André F S Luz, Ryan T Howard, Ravi Singh, Thomas J Burden, Erika Bernardini, Miguel Mateus-Pinheiro, Jens Petersen, Anders Gunnarsson, Jenny Gunnarsson, Anna Aagaard, Tove Sjögren, Sarah Maslen, Edward J Bartlett, Abigail F Iles, David M Smith, James S Scott, Mark Skehel, Andrew M Davis, Ana S Ressurreição, Rui Moreira, Cecília M P Rodrigues, Avinash R Shenoy, Edward W Tate

{"title":"Discovery and Validation of a Novel Class of Necroptosis Inhibitors Targeting RIPK1.","authors":"Lior Soday, Chotima Seripracharat, Janine L Gray, André F S Luz, Ryan T Howard, Ravi Singh, Thomas J Burden, Erika Bernardini, Miguel Mateus-Pinheiro, Jens Petersen, Anders Gunnarsson, Jenny Gunnarsson, Anna Aagaard, Tove Sjögren, Sarah Maslen, Edward J Bartlett, Abigail F Iles, David M Smith, James S Scott, Mark Skehel, Andrew M Davis, Ana S Ressurreição, Rui Moreira, Cecília M P Rodrigues, Avinash R Shenoy, Edward W Tate","doi":"10.1021/acschembio.5c00112","DOIUrl":"10.1021/acschembio.5c00112","url":null,"abstract":"Necroptosis is a form of programmed cell death that, when dysregulated, is associated with cancer and inflammatory and neurodegenerative diseases. Here, starting from hits identified from a phenotypic high-throughput screen for inhibitors of necroptosis, we synthesized a library of compounds containing a 7-phenylquinoline motif and validated their anti-necroptotic activity in a novel live-cell assay. Based on these data, we designed an optimized photoaffinity probe for target engagement studies and through biochemical and cell-based assays established receptor-interacting kinase 1 (RIPK1) as the cellular target, with inhibition of necroptosis arising from the prevention of RIPK1 autophosphorylation and activation. X-ray crystallography and mass spectrometry revealed that these compounds bind at the hinge region of the active conformation of RIPK1, establishing them as type I kinase inhibitors. In addition, we demonstrated in vitro synergy with type III kinase inhibitors, such as necrostatin-1 and found that lead compounds protected mice against acute inflammation in necroptosis models in vivo. Overall, we present a novel pharmacophore for inhibition of human RIPK1, a key protein involved in necroptosis, and provide a photoaffinity probe to explore RIPK1 target engagement in cells.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1527-1543"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional Conservation and Divergence of AlpJ-Family Oxygenases Catalyzing C-C Bond Cleavage in Atypical Angucycline Biosynthesis. 非典型安环素合成中催化C-C键断裂的alpj家族加氧酶的功能保守与分化

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-07-18 Epub Date: 2025-06-11 DOI: 10.1021/acschembio.5c00040

Shijie Shen, Changbiao Chi, Keqiang Fan, Qian Zhang, Yang Xu, Jinmin Gao, Huitao Hu, Lijun Wang, Donghui Yang, Ming Ma, Guohui Pan

{"title":"Functional Conservation and Divergence of AlpJ-Family Oxygenases Catalyzing C-C Bond Cleavage in Atypical Angucycline Biosynthesis.","authors":"Shijie Shen, Changbiao Chi, Keqiang Fan, Qian Zhang, Yang Xu, Jinmin Gao, Huitao Hu, Lijun Wang, Donghui Yang, Ming Ma, Guohui Pan","doi":"10.1021/acschembio.5c00040","DOIUrl":"10.1021/acschembio.5c00040","url":null,"abstract":"AlpJ-family oxygenases catalyze distinctive oxidative B-ring cleavage and rearrangement reactions during the biosynthesis of atypical angucycline natural products, which are characterized by unique chemical structures and diverse biological activities. While the individual functions of a few AlpJ-family enzymes have been reported, there is a lack of systematic exploration and functional comparison within this enzyme family, hindering a comprehensive understanding of the AlpJ-family oxygenases. In this study, we have systematically explored and analyzed AlpJ-family oxygenases, identifying 49 representative homologues, which can be classified into two distinct evolutionary groups. We revealed that enzymes from different groups exhibit clear functional differentiation, catalyzing the same angucycline substrate dehydrorabelomycin into distinct products, whereas enzymes within the same group display more similar catalytic functions with varying degrees of functional overlap. This underscores the intriguing functional conservation and divergence of the AlpJ-family oxygenases. In addition, we report the first crystal structure of a Group I enzyme, PenE. Structural analysis and site-directed mutagenesis identified key structural features and residues within AlpJ-family oxygenases, which harbor hydrophobic substrate-binding pockets at both the N- and C-termini, both of which are essential for function. Our findings provide valuable insights into the evolution, catalytic mechanisms, and functional divergence of this unique family of oxygenases. Further investigation of these newly identified AlpJ homologues and their associated biosynthetic gene clusters will facilitate the discovery of enzymes with unique catalytic mechanisms and bioactive atypical angucyclines with novel structures.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1481-1491"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Biphasic Cellular Response Triggered by Tetrandrine-Mediated Dysfunction and Lysophagic Clearance of Lysosomes. 由粉防己碱介导的功能障碍和溶酶体的溶噬清除引发的双相细胞反应。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-07-18 Epub Date: 2025-06-16 DOI: 10.1021/acschembio.5c00220

Zhe Yang, Tomoki Takahashi, Ayase Hoshino, Tatsuya Yamamoto, Hideyuki Shigemori, Yusaku Miyamae

{"title":"Biphasic Cellular Response Triggered by Tetrandrine-Mediated Dysfunction and Lysophagic Clearance of Lysosomes.","authors":"Zhe Yang, Tomoki Takahashi, Ayase Hoshino, Tatsuya Yamamoto, Hideyuki Shigemori, Yusaku Miyamae","doi":"10.1021/acschembio.5c00220","DOIUrl":"10.1021/acschembio.5c00220","url":null,"abstract":"Lysosomes play an important role in the degradation of cellular components and are correlated with various other physiological phenomena. Lysophagy is a cellular quality control system that maintains homeostasis by removing damaged lysosomes through autophagy. The involvement of lysosomal dysfunction in the pathogenesis of certain illnesses (e.g., neurodegeneration) highlights the potential of small molecules that regulate lysophagy as drug candidates. Here, we found that tetrandrine, a bis-benzylisoquinoline alkaloid, induces lysophagy, leading to the clearance of damaged lysosomes in mammalian cells. To visualize the target organelles of tetrandrine, we synthesized a chimeric compound in which tetrandrine was connected to boron-dipyrromethene via a polyethylene glycol linker. Flow cytometry analysis confirmed the cellular uptake of the synthesized probe. An organelle-staining assay showed that the fluorescent signal of the probe was specifically colocalized with lysosomes. Tetrandrine transiently increased the lysosomal pH level, which returned to normal at 24 h post treatment. Consistently, the level of mCherry-tagged galectin-3, a marker protein for lysophagy, transiently increased and then diminished under treatment with tetrandrine. Tetrandrine also induced dephosphorylation of transcription factor EB, a regulator of lysosomal biogenesis, promoting its translocation from the cytosol to the nucleus. These results suggest that tetrandrine induces a biphasic cellular response, first disrupting lysosomal function before facilitating cellular lysosomal homeostasis through lysophagy and lysosomal biogenesis. This dual effect distinguishes tetrandrine from existing lysosomal modulators.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1660-1668"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Tyrosine-Mediated Static and Dynamic Quenching of a Receptor Tyrosine Kinase Biosensor Reveals Inhibitor Binding Modes and Kinase Conformations. 酪氨酸介导的受体酪氨酸激酶生物传感器的静态和动态猝灭揭示了抑制剂结合模式和激酶构象。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-07-18 Epub Date: 2025-06-19 DOI: 10.1021/acschembio.5c00224

Zachary D Baker, Andrew R Thompson, David D Thomas, Nicholas M Levinson

{"title":"Tyrosine-Mediated Static and Dynamic Quenching of a Receptor Tyrosine Kinase Biosensor Reveals Inhibitor Binding Modes and Kinase Conformations.","authors":"Zachary D Baker, Andrew R Thompson, David D Thomas, Nicholas M Levinson","doi":"10.1021/acschembio.5c00224","DOIUrl":"10.1021/acschembio.5c00224","url":null,"abstract":"Conformational changes triggered by kinase inhibitors are a major factor driving specificity and efficacy, but few scalable methods exist for differentiating induced conformations and binding modes. Using the receptor tyrosine kinase MET, we show that three classes of inhibitors can be distinguished by their contrasting effects on static and dynamic quenching of a fluorescent dye attached to the activation loop. Quenching is mediated by tyrosine residues on the flexible activation loop, and inhibitor binding induces order in the loop, sequestering the tyrosines and differentially suppressing static and dynamic quenching in a manner that is dependent on the induced structural state. Type I MET inhibitors have a large static and moderate dynamic component, type II inhibitors have only a static component, and active-state-selective inhibitors relieve both components to similar extents. These distinct dequenching signatures allow the straightforward detection of each binding mode by using parallel steady-state and time-resolved fluorescence measurements. We show that this technique can be applied to rapidly assess the effects of resistance mutations on inhibitor binding and can report on the chemical interactions and conformational changes that drive these effects. Conservation of the three activation loop tyrosine residues across many receptor tyrosine kinases suggests that this approach has broad utility.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1683-1695"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0