Pub Date : 2025-11-11DOI: 10.1038/s41589-025-02061-5
Clostridium autoethanogenum produces ethanol from waste gases, but the biosynthetic pathway has been debated. Now, a combination of structural and biochemical data confirms that a key step in the ethanol biosynthesis pathway is acetate reduction by a tungsten-dependent aldehyde:ferredoxin oxido-reductase. This thermodynamically unfavorable reaction is counterbalanced by the coupling of ethanol synthesis with CO oxidation.
{"title":"A tungstopterin-containing enzyme has a key role in microbial ethanol biosynthesis","authors":"","doi":"10.1038/s41589-025-02061-5","DOIUrl":"10.1038/s41589-025-02061-5","url":null,"abstract":"Clostridium autoethanogenum produces ethanol from waste gases, but the biosynthetic pathway has been debated. Now, a combination of structural and biochemical data confirms that a key step in the ethanol biosynthesis pathway is acetate reduction by a tungsten-dependent aldehyde:ferredoxin oxido-reductase. This thermodynamically unfavorable reaction is counterbalanced by the coupling of ethanol synthesis with CO oxidation.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 1","pages":"17-18"},"PeriodicalIF":13.7,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491491","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}
Pub Date : 2025-11-11DOI: 10.1038/s41589-025-02064-2
Wyatt Beyers, Chi-Lun Chang
Approaches to study lipid composition with leaflet-specific resolution in living cells have been lacking. A new method — fluorogen-activating coincidence encounter sensing (FACES) — combines biorthogonal metabolic labeling with organelle-targeted fluorogen-activating proteins to selectively visualize lipids on leaflets of interest in any organelle.
{"title":"Unmasking the FACES of membrane bilayers","authors":"Wyatt Beyers, Chi-Lun Chang","doi":"10.1038/s41589-025-02064-2","DOIUrl":"10.1038/s41589-025-02064-2","url":null,"abstract":"Approaches to study lipid composition with leaflet-specific resolution in living cells have been lacking. A new method — fluorogen-activating coincidence encounter sensing (FACES) — combines biorthogonal metabolic labeling with organelle-targeted fluorogen-activating proteins to selectively visualize lipids on leaflets of interest in any organelle.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 1","pages":"11-12"},"PeriodicalIF":13.7,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485211","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}
Pub Date : 2025-11-05DOI: 10.1038/s41589-025-02073-1
We developed the prime editing tool PIE, which produces precise inversions of large genomic segments and chromosomal structural variations in mammalian cells. PIEv3b achieves high inversion efficiency and outperforms nuclease- and integrase-based methods, enabling chromosome reconfiguration from metacentric to telocentric forms.
{"title":"Prime editing-based tool enables precise genomic inversions at kilobase to chromosomal scale","authors":"","doi":"10.1038/s41589-025-02073-1","DOIUrl":"10.1038/s41589-025-02073-1","url":null,"abstract":"We developed the prime editing tool PIE, which produces precise inversions of large genomic segments and chromosomal structural variations in mammalian cells. PIEv3b achieves high inversion efficiency and outperforms nuclease- and integrase-based methods, enabling chromosome reconfiguration from metacentric to telocentric forms.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 2","pages":"167-168"},"PeriodicalIF":13.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145440865","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}
Pub Date : 2025-11-05DOI: 10.1038/s41589-025-02047-3
Timothy R. Stachowski, Marcus Fischer
Structure-based drug discovery relies on three-dimensional protein structures to provide the atomic blueprints for small-molecule design, indicating where to place each atom to maximize favorable interactions. The advent of cryo-cooling crystals in crystallography greatly accelerated the ease and accessibility of structural data, making it a mainstay of most drug discovery efforts. However, despite its successes, including producing numerous clinically successful molecules, cryo-cooled samples only tell part of the structural story: they may leave out dynamic details or introduce artifacts that may lead drug discovery campaigns astray. In this Perspective, we highlight recent studies characterizing temperature-sensitive structural phenomena observed by crystallography. We showcase how leveraging information on rare, hidden conformational states informs ligand discovery via molecular docking. This demonstrates the value of performing structural studies at elevated temperatures, closer to where biology occurs, to ‘unfreeze’ structural ensembles for drug discovery and design. This Perspective discusses how elevated-temperature crystallography uncovers hidden dynamic states of protein, ligand and water molecules, expanding insights into the protein conformational landscape for drug discovery and design.
{"title":"Unfreezing structural biology for drug discovery","authors":"Timothy R. Stachowski, Marcus Fischer","doi":"10.1038/s41589-025-02047-3","DOIUrl":"10.1038/s41589-025-02047-3","url":null,"abstract":"Structure-based drug discovery relies on three-dimensional protein structures to provide the atomic blueprints for small-molecule design, indicating where to place each atom to maximize favorable interactions. The advent of cryo-cooling crystals in crystallography greatly accelerated the ease and accessibility of structural data, making it a mainstay of most drug discovery efforts. However, despite its successes, including producing numerous clinically successful molecules, cryo-cooled samples only tell part of the structural story: they may leave out dynamic details or introduce artifacts that may lead drug discovery campaigns astray. In this Perspective, we highlight recent studies characterizing temperature-sensitive structural phenomena observed by crystallography. We showcase how leveraging information on rare, hidden conformational states informs ligand discovery via molecular docking. This demonstrates the value of performing structural studies at elevated temperatures, closer to where biology occurs, to ‘unfreeze’ structural ensembles for drug discovery and design. This Perspective discusses how elevated-temperature crystallography uncovers hidden dynamic states of protein, ligand and water molecules, expanding insights into the protein conformational landscape for drug discovery and design.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 2","pages":"169-179"},"PeriodicalIF":13.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145440928","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}
Pub Date : 2025-11-04DOI: 10.1038/s41589-025-02038-4
Agnese M. Nicoli, Michelle S. Frei
Fluorescence microscopy has become an indispensable tool to investigate the dynamics of macromolecules directly in living cells on length scales ranging from the nanoscale via super-resolution microscopy (SRM) to the macroscale by light sheet technology. Advances in these microscopy techniques and the desire to perform experiments with high spatial and temporal resolution in living cells increase the requirements imposed on the fluorophores used. Tailor-made synthetic small-molecule fluorophores in combination with innovative labeling strategies help to overcome these challenges and continue to push the boundaries in live-cell microscopy. This Review discusses important advances in improving the performance of synthetic fluorophores for live-cell applications and how synergistic effects can be produced by using clever labeling strategies. We detail how synthetic fluorophores advance different microscopy modalities including live-cell SRM and showcase how they can be implemented into biosensors to extend the frontiers of functional microscopy. Performing live-cell microscopy experiments with high spatial and temporal resolution requires fluorophores with highly optimized properties. This Review examines the progress in developing synthetic small-molecule fluorophores and how these in combination with innovative labeling strategies can advance chemical biology.
{"title":"Synthetic fluorophores for live-cell fluorescence microscopy and biosensing","authors":"Agnese M. Nicoli, Michelle S. Frei","doi":"10.1038/s41589-025-02038-4","DOIUrl":"10.1038/s41589-025-02038-4","url":null,"abstract":"Fluorescence microscopy has become an indispensable tool to investigate the dynamics of macromolecules directly in living cells on length scales ranging from the nanoscale via super-resolution microscopy (SRM) to the macroscale by light sheet technology. Advances in these microscopy techniques and the desire to perform experiments with high spatial and temporal resolution in living cells increase the requirements imposed on the fluorophores used. Tailor-made synthetic small-molecule fluorophores in combination with innovative labeling strategies help to overcome these challenges and continue to push the boundaries in live-cell microscopy. This Review discusses important advances in improving the performance of synthetic fluorophores for live-cell applications and how synergistic effects can be produced by using clever labeling strategies. We detail how synthetic fluorophores advance different microscopy modalities including live-cell SRM and showcase how they can be implemented into biosensors to extend the frontiers of functional microscopy. Performing live-cell microscopy experiments with high spatial and temporal resolution requires fluorophores with highly optimized properties. This Review examines the progress in developing synthetic small-molecule fluorophores and how these in combination with innovative labeling strategies can advance chemical biology.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 12","pages":"1846-1858"},"PeriodicalIF":13.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434533","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}
Pub Date : 2025-11-04DOI: 10.1038/s41589-025-02065-1
Jun Xiong, Neng-Bin Xie, Bi-Feng Yuan
Directed evolution is typically a slow and labor-intensive process that relies on multiple cycles of mutation to accelerate the development of desired protein traits. Now, a platform, named T7-ORACLE, has been developed that enables fast and scalable protein evolution.
{"title":"A super protein evolution engine","authors":"Jun Xiong, Neng-Bin Xie, Bi-Feng Yuan","doi":"10.1038/s41589-025-02065-1","DOIUrl":"10.1038/s41589-025-02065-1","url":null,"abstract":"Directed evolution is typically a slow and labor-intensive process that relies on multiple cycles of mutation to accelerate the development of desired protein traits. Now, a platform, named T7-ORACLE, has been developed that enables fast and scalable protein evolution.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 12","pages":"1842-1843"},"PeriodicalIF":13.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145440930","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}
Pub Date : 2025-11-03DOI: 10.1038/s41589-025-02051-7
Ananthan Sadagopan, Maximilian Carson, Eriks J. Zamurs, Nicholas Garaffo, Heng-Jui Chang, Stuart L. Schreiber, Matthew Meyerson, William J. Gibson
TP53 mutant cancers are associated with approximately half of cancer deaths. The most common mechanism of p53 inactivation involves missense mutations. Such mutations in TP53 result in a robust upregulation of the p53 protein. Here, we demonstrate an induced proximity approach to selectively kill TP53 mutant cells. This approach uses the increased abundance of p53 protein in TP53 mutant cancer cells to concentrate toxic molecules in these cells. We demonstrate this approach with a molecule that binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboring TP53Y220C mutations. The resulting bifunctional molecule promotes formation of a p53 Y220C –PLK1 ternary complex, mislocalizes PLK1, inhibits PLK1 activity, elicits selective G2/M arrest and induces apoptosis in TP53Y220C cells while sparing wild-type TP53 cells. These data exemplify a potentially generalizable framework for targeting TP53 missense mutations by leveraging mutant p53 protein abundance to induce cell death, independent of p53’s transcriptional activity.
{"title":"Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs","authors":"Ananthan Sadagopan, Maximilian Carson, Eriks J. Zamurs, Nicholas Garaffo, Heng-Jui Chang, Stuart L. Schreiber, Matthew Meyerson, William J. Gibson","doi":"10.1038/s41589-025-02051-7","DOIUrl":"https://doi.org/10.1038/s41589-025-02051-7","url":null,"abstract":"<jats:italic>TP53</jats:italic> mutant cancers are associated with approximately half of cancer deaths. The most common mechanism of p53 inactivation involves missense mutations. Such mutations in <jats:italic>TP53</jats:italic> result in a robust upregulation of the p53 protein. Here, we demonstrate an induced proximity approach to selectively kill <jats:italic>TP53</jats:italic> mutant cells. This approach uses the increased abundance of p53 protein in <jats:italic>TP53</jats:italic> mutant cancer cells to concentrate toxic molecules in these cells. We demonstrate this approach with a molecule that binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboring <jats:italic>TP53</jats:italic> <jats:sup>Y220C</jats:sup> mutations. The resulting bifunctional molecule promotes formation of a p53 <jats:sup>Y220C</jats:sup> –PLK1 ternary complex, mislocalizes PLK1, inhibits PLK1 activity, elicits selective G2/M arrest and induces apoptosis in <jats:italic>TP53</jats:italic> <jats:sup>Y220C</jats:sup> cells while sparing wild-type <jats:italic>TP53</jats:italic> cells. These data exemplify a potentially generalizable framework for targeting <jats:italic>TP53</jats:italic> missense mutations by leveraging mutant p53 protein abundance to induce cell death, independent of p53’s transcriptional activity.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"79 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427669","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}
Pub Date : 2025-10-31DOI: 10.1038/s41589-025-02060-6
Tristan Yoder, Elizabeth A. Mills, Wan-Lin Lo
{"title":"Intrinsically ordered domains expand the CAR T cell toolbox","authors":"Tristan Yoder, Elizabeth A. Mills, Wan-Lin Lo","doi":"10.1038/s41589-025-02060-6","DOIUrl":"https://doi.org/10.1038/s41589-025-02060-6","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"17 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404770","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}
Pub Date : 2025-10-31DOI: 10.1038/s41589-025-02063-3
Ziqi Gao, Tianzhen Li, Hao Ye, William Shu Ching Ngai, Huijie Wang, Peng R. Chen, Jie Wang
Reprogramming the specificity of proteases toward alternative target sequences could enable an array of exciting applications, ranging from proteome editing to therapeutic interventions. Here we report an in vivo life–death selection system for protease reprogramming using the toxic N-terminal domain of gasdermin D (GD-N) protein as a selection marker. The approach is a modular system that can be used to cover the protease mutational diversity in the billions through only a few cycles of directed evolution. By inserting the desired cleavage sequence into the loop region of the GD-N protein, which is toxic to host bacteria cells, the system selects for efficient substrate cleavage—rendering GD-N nontoxic—by enrichment of bacteria in liquid culture. Using the tobacco etch virus protease (TEVp) and corresponding substrate sequence as a model, we demonstrated that our platform could select and enrich an efficient protease variant millionfold after a single round of selection. We also evolve TEVp to cut sequences on target proteins with known pathological roles. An in vivo selection system based on the toxicity regulation of the N-terminal domain of gasdermin D and evolution of tobacco etch virus protease (TEVp) has been developed. The method enables development of a TEVp capable of precise cleavage of specific sequences on target proteins.
{"title":"A gasdermin-based life–death evolution system for reprogramming protease specificity","authors":"Ziqi Gao, Tianzhen Li, Hao Ye, William Shu Ching Ngai, Huijie Wang, Peng R. Chen, Jie Wang","doi":"10.1038/s41589-025-02063-3","DOIUrl":"10.1038/s41589-025-02063-3","url":null,"abstract":"Reprogramming the specificity of proteases toward alternative target sequences could enable an array of exciting applications, ranging from proteome editing to therapeutic interventions. Here we report an in vivo life–death selection system for protease reprogramming using the toxic N-terminal domain of gasdermin D (GD-N) protein as a selection marker. The approach is a modular system that can be used to cover the protease mutational diversity in the billions through only a few cycles of directed evolution. By inserting the desired cleavage sequence into the loop region of the GD-N protein, which is toxic to host bacteria cells, the system selects for efficient substrate cleavage—rendering GD-N nontoxic—by enrichment of bacteria in liquid culture. Using the tobacco etch virus protease (TEVp) and corresponding substrate sequence as a model, we demonstrated that our platform could select and enrich an efficient protease variant millionfold after a single round of selection. We also evolve TEVp to cut sequences on target proteins with known pathological roles. An in vivo selection system based on the toxicity regulation of the N-terminal domain of gasdermin D and evolution of tobacco etch virus protease (TEVp) has been developed. The method enables development of a TEVp capable of precise cleavage of specific sequences on target proteins.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 1","pages":"87-96"},"PeriodicalIF":13.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145411624","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}
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