Pub Date : 2026-01-26DOI: 10.1038/s41589-025-02136-3
Cyntia Taveneau, Her Xiang Chai, Jovita D’Silva, Rebecca S. Bamert, Honglin Chen, Brooke K. Hayes, Roland W. Calvert, Jacob Purcell, Daniel J. Curwen, Fabian Munder, Lisandra L. Martin, Jeremy J. Barr, Joseph Rosenbluh, Mohamed Fareh, Rhys Grinter, Gavin J. Knott
CRISPR–Cas systems are transformative tools for gene editing that can be tuned or controlled by anti-CRISPRs (Acrs)—phage-derived inhibitors that regulate CRISPR–Cas activity. However, Acrs that can inhibit biotechnologically relevant CRISPR systems are relatively rare and challenging to discover. To overcome this limitation, we describe a highly successful and rapid approach that leverages de novo protein design to develop new-to-nature proteins for controlling CRISPR–Cas activity. Here, using Leptotrichiabuccalis CRISPR–Cas13a as a representative example, we demonstrate that Acrs designed using artificial intelligence (AIcrs) are capable of highly potent and specific inhibition of CRISPR–Cas13a nuclease activity. We present a comprehensive workflow for design validation and demonstrate AIcr functionality in controlling CRISPR–Cas13 activity in bacterial and human cells. The ability to design bespoke inhibitors of Cas effectors will contribute to the ongoing development of CRISPR–Cas tools in diverse applications across research, medicine, agriculture and microbiology.
{"title":"De novo design of potent CRISPR–Cas13 inhibitors","authors":"Cyntia Taveneau, Her Xiang Chai, Jovita D’Silva, Rebecca S. Bamert, Honglin Chen, Brooke K. Hayes, Roland W. Calvert, Jacob Purcell, Daniel J. Curwen, Fabian Munder, Lisandra L. Martin, Jeremy J. Barr, Joseph Rosenbluh, Mohamed Fareh, Rhys Grinter, Gavin J. Knott","doi":"10.1038/s41589-025-02136-3","DOIUrl":"https://doi.org/10.1038/s41589-025-02136-3","url":null,"abstract":"CRISPR–Cas systems are transformative tools for gene editing that can be tuned or controlled by anti-CRISPRs (Acrs)—phage-derived inhibitors that regulate CRISPR–Cas activity. However, Acrs that can inhibit biotechnologically relevant CRISPR systems are relatively rare and challenging to discover. To overcome this limitation, we describe a highly successful and rapid approach that leverages de novo protein design to develop new-to-nature proteins for controlling CRISPR–Cas activity. Here, using <jats:italic>Leptotrichia</jats:italic> <jats:italic>buccalis</jats:italic> CRISPR–Cas13a as a representative example, we demonstrate that Acrs designed using artificial intelligence (AIcrs) are capable of highly potent and specific inhibition of CRISPR–Cas13a nuclease activity. We present a comprehensive workflow for design validation and demonstrate AIcr functionality in controlling CRISPR–Cas13 activity in bacterial and human cells. The ability to design bespoke inhibitors of Cas effectors will contribute to the ongoing development of CRISPR–Cas tools in diverse applications across research, medicine, agriculture and microbiology.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"274 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048303","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 : 2026-01-22DOI: 10.1038/s41589-025-02096-8
Indigo C Geohring, Pengxin Chai, Bharat R Iyer, William D Ton, Jun Yang, Amy H Ide, Sydney C George, Jaiveer S Bagri, Samuel V Baird, Kai Zhang, Steven M Markus
Dynein-1 is a microtubule motor that transports numerous cytoplasmic cargoes. Activation of motility requires it first overcome an autoinhibited state before its assembly with dynactin and a cargo adaptor. Studies suggest that Lis1 may relieve dynein's autoinhibited state, although evidence for this is lacking. We first determined the rules governing dynein-Lis1 binding, revealing that their binding affinity is regulated by the nucleotide-bound states of each of three nucleotide-binding pockets within dynein. We also found that distinct nucleotide 'codes' coordinate their binding stoichiometry by impacting binding affinity at two different sites within the dynein motor domain. Electron microscopy revealed that a 1 dynein:1 Lis1 complex directly promotes an uninhibited conformational state of dynein, whereas a 1:2 complex resembles the autoinhibited state. Cryo-electron microscopy revealed that the structural basis for Lis1 opening dynein relies on interactions with the linker domain. Our work reveals the biochemical basis by which Lis1 relieves dynein autoinhibition.
{"title":"A nucleotide code governs Lis1's ability to relieve dynein autoinhibition.","authors":"Indigo C Geohring, Pengxin Chai, Bharat R Iyer, William D Ton, Jun Yang, Amy H Ide, Sydney C George, Jaiveer S Bagri, Samuel V Baird, Kai Zhang, Steven M Markus","doi":"10.1038/s41589-025-02096-8","DOIUrl":"10.1038/s41589-025-02096-8","url":null,"abstract":"<p><p>Dynein-1 is a microtubule motor that transports numerous cytoplasmic cargoes. Activation of motility requires it first overcome an autoinhibited state before its assembly with dynactin and a cargo adaptor. Studies suggest that Lis1 may relieve dynein's autoinhibited state, although evidence for this is lacking. We first determined the rules governing dynein-Lis1 binding, revealing that their binding affinity is regulated by the nucleotide-bound states of each of three nucleotide-binding pockets within dynein. We also found that distinct nucleotide 'codes' coordinate their binding stoichiometry by impacting binding affinity at two different sites within the dynein motor domain. Electron microscopy revealed that a 1 dynein:1 Lis1 complex directly promotes an uninhibited conformational state of dynein, whereas a 1:2 complex resembles the autoinhibited state. Cryo-electron microscopy revealed that the structural basis for Lis1 opening dynein relies on interactions with the linker domain. Our work reveals the biochemical basis by which Lis1 relieves dynein autoinhibition.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030312","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}
Thymine DNA glycosylase (TDG) is a multifaceted protein involved in base-excision repair, DNA demethylation and transcriptional regulation, with key roles in embryonic development and tumorigenesis. However, the mechanisms underlying its role in cancer progression and the therapeutic applications targeting TDG remain largely unknown. Here we demonstrate that targeting TDG induces synthetic lethality in p53-deficient cancers. We developed C-271, a first-in-class, small-molecule inhibitor that covalently binds to TDG, disrupting its DNA-binding capability. C-271 exhibits potent therapeutic efficacy in suppressing p53-deficient tumors. Mechanistically, TDG and p53 redundantly promote the transcription of DHX9, an RNA helicase that resolves double-stranded RNA (dsRNA). TDG inhibition in p53-deficient cancer cells leads to DHX9 downregulation and, thus, aberrant dsRNA accumulation, which activates the RIG-I/MDA5-MAVS sensing pathway, resulting in tumor suppression and enhanced antitumor immunity. These findings highlight the synthetic lethality between TDG and p53, positioning TDG inhibition as a promising therapeutic strategy for p53-deficient cancers.
{"title":"Targeting thymine DNA glycosylase induces synthetic lethality in p53-deficient cancers.","authors":"Jia-Xin Zhou,Zhen-Yu Shao,Lin Zhang,Jian-Nan Guo,Meng Wang,Qin Xu,Yi-Qin Wang,Qing Xu,Dan Zhou,Sheng-Xiang Ren,Yan-Hao Yu,Zhi-Hao Lu,Guo-Zheng Pang,Yao Cao,Yi-Lin Liu,Bin Zhou,Hong-Bin Ji,Yi-Han Chen,Hai-Ping Wu,Guo-Liang Xu,Liang Zhang,Ya-Rui Du","doi":"10.1038/s41589-025-02100-1","DOIUrl":"https://doi.org/10.1038/s41589-025-02100-1","url":null,"abstract":"Thymine DNA glycosylase (TDG) is a multifaceted protein involved in base-excision repair, DNA demethylation and transcriptional regulation, with key roles in embryonic development and tumorigenesis. However, the mechanisms underlying its role in cancer progression and the therapeutic applications targeting TDG remain largely unknown. Here we demonstrate that targeting TDG induces synthetic lethality in p53-deficient cancers. We developed C-271, a first-in-class, small-molecule inhibitor that covalently binds to TDG, disrupting its DNA-binding capability. C-271 exhibits potent therapeutic efficacy in suppressing p53-deficient tumors. Mechanistically, TDG and p53 redundantly promote the transcription of DHX9, an RNA helicase that resolves double-stranded RNA (dsRNA). TDG inhibition in p53-deficient cancer cells leads to DHX9 downregulation and, thus, aberrant dsRNA accumulation, which activates the RIG-I/MDA5-MAVS sensing pathway, resulting in tumor suppression and enhanced antitumor immunity. These findings highlight the synthetic lethality between TDG and p53, positioning TDG inhibition as a promising therapeutic strategy for p53-deficient cancers.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"67 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021696","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 : 2026-01-22DOI: 10.1038/s41589-025-02101-0
Simon D Schwarz
{"title":"Targeting transcriptional plasticity in cancer.","authors":"Simon D Schwarz","doi":"10.1038/s41589-025-02101-0","DOIUrl":"https://doi.org/10.1038/s41589-025-02101-0","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030294","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 : 2026-01-20DOI: 10.1038/s41589-025-02113-w
Zhen Li,Himanshi Chawla,Lucia Di Vagno,Aisling Ní Cheallaigh,Meg Critcher,Douglas Sammon,Edgar Gonzalez-Rodriguez,David C Briggs,Nara Chung,Vincent Chang,Keira E Mahoney,Anna Cioce,Ganka Bineva-Todd,Pei-Ying Wang,Yi-Chang Liu,Lloyd D Murphy,Yen-Hsi Chen,Yoshiki Narimatsu,Rebecca L Miller,Lianne I Willems,Stacy A Malaker,Mia L Huang,Gavin J Miller,Erhard Hohenester,Benjamin Schumann
Mammalian cells receive signaling instructions through interactions on their surfaces. Proteoglycans are critical to these interactions, carrying long glycosaminoglycans that recruit signaling molecules. Biosynthetic redundancy in the first glycosylation step by two xylosyltransferases XT1/2 complicates annotation of proteoglycans. Here we develop a chemical genetic strategy that manipulates the glycan attachment site of cellular proteoglycans. Through a bump-and-hole tactic, we engineer the two isoenzymes XT1 and XT2 to specifically transfer the chemically tagged xylose analog 6AzGlc to target proteins. The tag contains a bioorthogonal functionality, allowing to visualize and profile target proteins in mammalian cells. Unlike xylose analogs, 6AzGlc is amenable to cellular nucleotide-sugar biosynthesis, establishing the XT1/2 bump-and-hole tactic in cells. The approach allows pinpointing glycosylation sites by mass spectrometry and exploiting the chemical handle to manufacture proteoglycans with defined glycosaminoglycan chains for cellular applications. Engineered XT enzymes permit an orthogonal view into proteoglycan biology through conventional techniques in biochemistry.
{"title":"Xylosyltransferase engineering to manipulate proteoglycans in mammalian cells.","authors":"Zhen Li,Himanshi Chawla,Lucia Di Vagno,Aisling Ní Cheallaigh,Meg Critcher,Douglas Sammon,Edgar Gonzalez-Rodriguez,David C Briggs,Nara Chung,Vincent Chang,Keira E Mahoney,Anna Cioce,Ganka Bineva-Todd,Pei-Ying Wang,Yi-Chang Liu,Lloyd D Murphy,Yen-Hsi Chen,Yoshiki Narimatsu,Rebecca L Miller,Lianne I Willems,Stacy A Malaker,Mia L Huang,Gavin J Miller,Erhard Hohenester,Benjamin Schumann","doi":"10.1038/s41589-025-02113-w","DOIUrl":"https://doi.org/10.1038/s41589-025-02113-w","url":null,"abstract":"Mammalian cells receive signaling instructions through interactions on their surfaces. Proteoglycans are critical to these interactions, carrying long glycosaminoglycans that recruit signaling molecules. Biosynthetic redundancy in the first glycosylation step by two xylosyltransferases XT1/2 complicates annotation of proteoglycans. Here we develop a chemical genetic strategy that manipulates the glycan attachment site of cellular proteoglycans. Through a bump-and-hole tactic, we engineer the two isoenzymes XT1 and XT2 to specifically transfer the chemically tagged xylose analog 6AzGlc to target proteins. The tag contains a bioorthogonal functionality, allowing to visualize and profile target proteins in mammalian cells. Unlike xylose analogs, 6AzGlc is amenable to cellular nucleotide-sugar biosynthesis, establishing the XT1/2 bump-and-hole tactic in cells. The approach allows pinpointing glycosylation sites by mass spectrometry and exploiting the chemical handle to manufacture proteoglycans with defined glycosaminoglycan chains for cellular applications. Engineered XT enzymes permit an orthogonal view into proteoglycan biology through conventional techniques in biochemistry.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"59 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005477","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 : 2026-01-19DOI: 10.1038/s41589-025-02129-2
Kiroo Shin, Da Bean Han, Hyun Woo Kim, Jungwook Kim
Modifications at the wobble position of transfer RNA (tRNA) are critical for accurate codon recognition and efficient translation. 5-Hydroxyuridine serves as a key intermediate for more complex wobble uridine derivatives commonly found in bacterial tRNAs and is synthesized by either prephenate-dependent TrhP or dioxygen-dependent TrhO. Despite its biological importance, structural and mechanistic insights into these enzymes have remained elusive. Here, we report the cryo-electron microscopy structure of Bacillus subtilis TrhO-tRNAAla complex. Combined with biochemical analyses, our results reveal that TrhO functions without any metal or organic cofactor, unlike most other oxygenases. We propose that the conserved C179 reacts with dioxygen to form a thiohydroperoxy intermediate, which is cleaved to produce 5-hydroxyuridine and a sulfenic acid at C179. The oxidized cysteine subsequently forms a disulfide bond with the adjacent C185, protecting the catalytic cysteine from irreversible overoxidation. These findings broaden our understanding of cofactor-independent dioxygen use in aromatic ring hydroxylation.
{"title":"Unconventional monooxygenation by the O<sub>2</sub>-dependent tRNA wobble uridine hydroxylase TrhO.","authors":"Kiroo Shin, Da Bean Han, Hyun Woo Kim, Jungwook Kim","doi":"10.1038/s41589-025-02129-2","DOIUrl":"https://doi.org/10.1038/s41589-025-02129-2","url":null,"abstract":"<p><p>Modifications at the wobble position of transfer RNA (tRNA) are critical for accurate codon recognition and efficient translation. 5-Hydroxyuridine serves as a key intermediate for more complex wobble uridine derivatives commonly found in bacterial tRNAs and is synthesized by either prephenate-dependent TrhP or dioxygen-dependent TrhO. Despite its biological importance, structural and mechanistic insights into these enzymes have remained elusive. Here, we report the cryo-electron microscopy structure of Bacillus subtilis TrhO-tRNA<sup>Ala</sup> complex. Combined with biochemical analyses, our results reveal that TrhO functions without any metal or organic cofactor, unlike most other oxygenases. We propose that the conserved C179 reacts with dioxygen to form a thiohydroperoxy intermediate, which is cleaved to produce 5-hydroxyuridine and a sulfenic acid at C179. The oxidized cysteine subsequently forms a disulfide bond with the adjacent C185, protecting the catalytic cysteine from irreversible overoxidation. These findings broaden our understanding of cofactor-independent dioxygen use in aromatic ring hydroxylation.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003794","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 : 2026-01-16DOI: 10.1038/s41589-025-02085-x
Markus Müller, Konstantin Niemeyer, Navin K. Ojha, Sebastian A. Porav, Deivanayagabarathy Vinayagam, Nicole Urban, Fanny Büchau, Katharina Oleinikov, Mazen Makke, Claudia C. Bauer, Aidan V. Johnson, Stephen P. Muench, Frank Zufall, Dieter Bruns, Yvonne Schwarz, Stefan Raunser, Trese Leinders-Zufall, Robin S. Bon, Michael Schaefer, Oliver Thorn-Seshold
Precisely probing the endogenous roles of target proteins is crucial for biological research. Photochemical tools can be photoactuated with high spatiotemporal resolution but often they are unreliable in vivo because spatiotemporal variations of reagent concentration result in inhomogeneous bioactivity. We now describe ideal efficacy photoswitching, a paradigm that internally compensates for reagent concentration by self-competitive binding, allowing purely wavelength-dependent chromocontrol over bioactivity that is consistent from cell culture to deep tissues. We demonstrate this with photoswitches for endogenous transient receptor potential (TRP) C4 and C5 ion channels, reproducibly delivering strong agonism under 360-nm illumination, weak agonism under 385-nm illumination and strong antagonism under 440-nm illumination. These ligands unlock a range of high-precision investigations in TRP biology, from neuronal activity to exocytosis, reproductive signaling and smooth muscle contractility. The ideal efficacy photoswitching paradigm should also unlock high-performance chromocontrol over a wide range of sensory or signaling channels and receptors even in vivo. Using chemical photoswitchable reagents to exert purely wavelength-dependent control over biological systems in deep tissue and in vivo requires a concentration-independent design paradigm. Here, such photoswitchable ligands are realized by ensuring that E/Z isomers have opposing efficacies yet similarly high affinity, allowing them to probe transient receptor potential C4 and C5 channel functions up to the tissue level.
{"title":"Ideal efficacy photoswitching for chromocontrol of TRPC4/5 channel functions in live tissues","authors":"Markus Müller, Konstantin Niemeyer, Navin K. Ojha, Sebastian A. Porav, Deivanayagabarathy Vinayagam, Nicole Urban, Fanny Büchau, Katharina Oleinikov, Mazen Makke, Claudia C. Bauer, Aidan V. Johnson, Stephen P. Muench, Frank Zufall, Dieter Bruns, Yvonne Schwarz, Stefan Raunser, Trese Leinders-Zufall, Robin S. Bon, Michael Schaefer, Oliver Thorn-Seshold","doi":"10.1038/s41589-025-02085-x","DOIUrl":"10.1038/s41589-025-02085-x","url":null,"abstract":"Precisely probing the endogenous roles of target proteins is crucial for biological research. Photochemical tools can be photoactuated with high spatiotemporal resolution but often they are unreliable in vivo because spatiotemporal variations of reagent concentration result in inhomogeneous bioactivity. We now describe ideal efficacy photoswitching, a paradigm that internally compensates for reagent concentration by self-competitive binding, allowing purely wavelength-dependent chromocontrol over bioactivity that is consistent from cell culture to deep tissues. We demonstrate this with photoswitches for endogenous transient receptor potential (TRP) C4 and C5 ion channels, reproducibly delivering strong agonism under 360-nm illumination, weak agonism under 385-nm illumination and strong antagonism under 440-nm illumination. These ligands unlock a range of high-precision investigations in TRP biology, from neuronal activity to exocytosis, reproductive signaling and smooth muscle contractility. The ideal efficacy photoswitching paradigm should also unlock high-performance chromocontrol over a wide range of sensory or signaling channels and receptors even in vivo. Using chemical photoswitchable reagents to exert purely wavelength-dependent control over biological systems in deep tissue and in vivo requires a concentration-independent design paradigm. Here, such photoswitchable ligands are realized by ensuring that E/Z isomers have opposing efficacies yet similarly high affinity, allowing them to probe transient receptor potential C4 and C5 channel functions up to the tissue level.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 2","pages":"180-191"},"PeriodicalIF":13.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41589-025-02085-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1038/s41589-025-02087-9
Jana Volarić, Wiktor Szymanski
Ideal efficacy photoswitching is introduced as a concept in controlling protein activity with light. Largely independent of the concentration of a light-responsive compound, it enables TRPC4 and TRPC5 channels to be precisely agonized or antagonized depending on the color of light used.
{"title":"Pick a color to control TRP channels","authors":"Jana Volarić, Wiktor Szymanski","doi":"10.1038/s41589-025-02087-9","DOIUrl":"10.1038/s41589-025-02087-9","url":null,"abstract":"Ideal efficacy photoswitching is introduced as a concept in controlling protein activity with light. Largely independent of the concentration of a light-responsive compound, it enables TRPC4 and TRPC5 channels to be precisely agonized or antagonized depending on the color of light used.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 2","pages":"163-164"},"PeriodicalIF":13.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986232","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 : 2026-01-13DOI: 10.1038/s41589-025-02131-8
Lu Hu, Jinyu Lin, Liping Sun, Alison M. Berezuk, Katharine S. Tuttle, Xing Zhu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Pan Li, Yang Sun, Lisheng Ni, Jianan Zhang, Dazhi Tan, Hiroaki Wakimoto, Daniel P. Cahill, Xiaochen Bai, Xuelian Luo, John M. Asara, Sriram Subramaniam, Yibing Shan, Xu Wu
Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.
{"title":"Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells","authors":"Lu Hu, Jinyu Lin, Liping Sun, Alison M. Berezuk, Katharine S. Tuttle, Xing Zhu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Pan Li, Yang Sun, Lisheng Ni, Jianan Zhang, Dazhi Tan, Hiroaki Wakimoto, Daniel P. Cahill, Xiaochen Bai, Xuelian Luo, John M. Asara, Sriram Subramaniam, Yibing Shan, Xu Wu","doi":"10.1038/s41589-025-02131-8","DOIUrl":"https://doi.org/10.1038/s41589-025-02131-8","url":null,"abstract":"Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"385 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956335","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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