Pub Date : 2024-08-22DOI: 10.1038/s42004-024-01264-6
Judit E. Šponer, Rémi Coulon, Michal Otyepka, Jiří Šponer, Alexander F. Siegle, Oliver Trapp, Katarzyna Ślepokura, Zbyněk Zdráhal, Ondrej Šedo
Because of their unique proton-conductivity, chains of phosphoric acid molecules are excellent proton-transfer catalysts. Here we demonstrate that this property could have been exploited for the prebiotic synthesis of the first oligopeptide sequences on our planet. Our results suggest that drying highly diluted solutions containing amino acids (like glycine, histidine and arginine) and phosphates in comparable concentrations at elevated temperatures (ca. 80 °C) in an acidic environment could lead to the accumulation of amino acid:phosphoric acid crystalline salts. Subsequent heating of these materials at 100 °C for 1–3 days results in the formation of oligoglycines consisting of up to 24 monomeric units, while arginine and histidine form shorter oligomers (up to trimers) only. Overall, our results suggest that combining the catalytic effect of phosphate chains with the crystalline order present in amino acid:phosphoric acid salts represents a viable solution that could be utilized to generate the first oligopeptide sequences in a mild acidic hydrothermal field scenario. Further, we propose that crystallization could help overcoming cyclic oligomer formation that is a generally known bottleneck of prebiotic polymerization processes preventing further chain growth. Phosphates are fundamental building blocks of ribonucleic acids and excellent catalysts for proton transfer reactions. Here, the authors report that the combination of the catalytic effect of phosphates with the entropic effect of crystallization can be exploited to facilitate formation of oligopeptides from the crystalline salts of phosphoric acid with amino acids under mild conditions.
{"title":"Phosphoric acid salts of amino acids as a source of oligopeptides on the early Earth","authors":"Judit E. Šponer, Rémi Coulon, Michal Otyepka, Jiří Šponer, Alexander F. Siegle, Oliver Trapp, Katarzyna Ślepokura, Zbyněk Zdráhal, Ondrej Šedo","doi":"10.1038/s42004-024-01264-6","DOIUrl":"10.1038/s42004-024-01264-6","url":null,"abstract":"Because of their unique proton-conductivity, chains of phosphoric acid molecules are excellent proton-transfer catalysts. Here we demonstrate that this property could have been exploited for the prebiotic synthesis of the first oligopeptide sequences on our planet. Our results suggest that drying highly diluted solutions containing amino acids (like glycine, histidine and arginine) and phosphates in comparable concentrations at elevated temperatures (ca. 80 °C) in an acidic environment could lead to the accumulation of amino acid:phosphoric acid crystalline salts. Subsequent heating of these materials at 100 °C for 1–3 days results in the formation of oligoglycines consisting of up to 24 monomeric units, while arginine and histidine form shorter oligomers (up to trimers) only. Overall, our results suggest that combining the catalytic effect of phosphate chains with the crystalline order present in amino acid:phosphoric acid salts represents a viable solution that could be utilized to generate the first oligopeptide sequences in a mild acidic hydrothermal field scenario. Further, we propose that crystallization could help overcoming cyclic oligomer formation that is a generally known bottleneck of prebiotic polymerization processes preventing further chain growth. Phosphates are fundamental building blocks of ribonucleic acids and excellent catalysts for proton transfer reactions. Here, the authors report that the combination of the catalytic effect of phosphates with the entropic effect of crystallization can be exploited to facilitate formation of oligopeptides from the crystalline salts of phosphoric acid with amino acids under mild conditions.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-8"},"PeriodicalIF":5.9,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01264-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-16DOI: 10.1038/s42004-024-01273-5
Jianbing Jiang, Diana Czuchry, Yanxia Ru, Huipai Peng, Junfeng Shen, Teng Wang, Wenjuan Zhao, Weihua Chen, Sen-Fang Sui, Yaowang Li, Nan Li
The gut microbiota offers an extensive resource of enzymes, but many remain uncharacterized. To distinguish the activities of similar annotated proteins and mine the potentially applicable ones in the microbiome, we applied an effective Activity-Based Metaproteomics (ABMP) strategy using a specific activity-based probe (ABP) to screen the entire gut microbiome for directly discovering active enzymes and their potential applications, not for exploring host-microbiome interactions. By using an activity-based cyclophellitol aziridine probe specific to α-galactosidases (AGAL), we successfully identified and characterized several gut microbiota enzymes possessing AGAL activities. Cryo-electron microscopy analysis of a newly characterized enzyme (AGLA5) revealed the covalent binding conformations between the AGAL5 active site and the cyclophellitol aziridine ABP, which could provide insights into the enzyme’s catalytic mechanism. The four newly characterized AGALs have diverse potential activities, including raffinose family oligosaccharides (RFOs) hydrolysis and enzymatic blood group transformation. Collectively, we present a ABMP platform that facilitates gut microbiota AGALs discovery, biochemical activity annotations and potential industrial or biopharmaceutical applications. The gut microbiota offers an extensive resource of enzymes, however, many remain uncharacterized. Here, the authors apply an activity-based metaproteomics strategy using an activity-based cyclophellitol aziridine probe specific to α-galactosidases (AGAL), and identify and characterize several gut microbiota enzymes possessing AGAL activities.
{"title":"Activity-based metaproteomics driven discovery and enzymological characterization of potential α-galactosidases in the mouse gut microbiome","authors":"Jianbing Jiang, Diana Czuchry, Yanxia Ru, Huipai Peng, Junfeng Shen, Teng Wang, Wenjuan Zhao, Weihua Chen, Sen-Fang Sui, Yaowang Li, Nan Li","doi":"10.1038/s42004-024-01273-5","DOIUrl":"10.1038/s42004-024-01273-5","url":null,"abstract":"The gut microbiota offers an extensive resource of enzymes, but many remain uncharacterized. To distinguish the activities of similar annotated proteins and mine the potentially applicable ones in the microbiome, we applied an effective Activity-Based Metaproteomics (ABMP) strategy using a specific activity-based probe (ABP) to screen the entire gut microbiome for directly discovering active enzymes and their potential applications, not for exploring host-microbiome interactions. By using an activity-based cyclophellitol aziridine probe specific to α-galactosidases (AGAL), we successfully identified and characterized several gut microbiota enzymes possessing AGAL activities. Cryo-electron microscopy analysis of a newly characterized enzyme (AGLA5) revealed the covalent binding conformations between the AGAL5 active site and the cyclophellitol aziridine ABP, which could provide insights into the enzyme’s catalytic mechanism. The four newly characterized AGALs have diverse potential activities, including raffinose family oligosaccharides (RFOs) hydrolysis and enzymatic blood group transformation. Collectively, we present a ABMP platform that facilitates gut microbiota AGALs discovery, biochemical activity annotations and potential industrial or biopharmaceutical applications. The gut microbiota offers an extensive resource of enzymes, however, many remain uncharacterized. Here, the authors apply an activity-based metaproteomics strategy using an activity-based cyclophellitol aziridine probe specific to α-galactosidases (AGAL), and identify and characterize several gut microbiota enzymes possessing AGAL activities.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-15"},"PeriodicalIF":5.9,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01273-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141991749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-16DOI: 10.1038/s42004-024-01263-7
Qi Hao, Manoj K. Rathinaswamy, Kelly L. Klinge, Matthew Bratkowski, Amirhossein Mafi, Christina K. Baumgartner, Keith M. Hamel, Gesine K. Veits, Rinku Jain, Claudio Catalano, Mark Fitzgerald, Alexander W. Hird, Eunice Park, Harit U. Vora, James A. Henderson, Kenton Longenecker, Charles W. Hutchins, Wei Qiu, Giovanna Scapin, Qi Sun, Vincent S. Stoll, Chaohong Sun, Ping Li, Dan Eaton, David Stokoe, Stewart L. Fisher, Christopher G. Nasveschuk, Marcia Paddock, Michael E. Kort
PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4CRBN, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes. PTPN2 (protein tyrosine phosphatase non-receptor type 2) and PTPN1 are attractive immuno-oncology targets, however, targeting PTPN2/N1 poses significant challenges. Here, the authors report the development of potent PTPN2/N1 heterobifunctional degraders and reveal biochemical and structural insights into the formation of ternary structures with cereblon E3 ligase by X-ray diffraction, cryo-EM and MD simulations.
{"title":"Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex","authors":"Qi Hao, Manoj K. Rathinaswamy, Kelly L. Klinge, Matthew Bratkowski, Amirhossein Mafi, Christina K. Baumgartner, Keith M. Hamel, Gesine K. Veits, Rinku Jain, Claudio Catalano, Mark Fitzgerald, Alexander W. Hird, Eunice Park, Harit U. Vora, James A. Henderson, Kenton Longenecker, Charles W. Hutchins, Wei Qiu, Giovanna Scapin, Qi Sun, Vincent S. Stoll, Chaohong Sun, Ping Li, Dan Eaton, David Stokoe, Stewart L. Fisher, Christopher G. Nasveschuk, Marcia Paddock, Michael E. Kort","doi":"10.1038/s42004-024-01263-7","DOIUrl":"10.1038/s42004-024-01263-7","url":null,"abstract":"PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4CRBN, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes. PTPN2 (protein tyrosine phosphatase non-receptor type 2) and PTPN1 are attractive immuno-oncology targets, however, targeting PTPN2/N1 poses significant challenges. Here, the authors report the development of potent PTPN2/N1 heterobifunctional degraders and reveal biochemical and structural insights into the formation of ternary structures with cereblon E3 ligase by X-ray diffraction, cryo-EM and MD simulations.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-16"},"PeriodicalIF":5.9,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01263-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141991747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1038/s42004-024-01266-4
Shiqi Wang, Mariia V. Shcherbii, Sami-Pekka Hirvonen, Gudrun Silvennoinen, Mirkka Sarparanta, Hélder A. Santos
Efficient intracellular delivery is crucial for biotherapeutics, such as proteins, oligonucleotides, and CRISPR/Cas9 gene-editing systems, to achieve their efficacy. Despite the great efforts of developing new intracellular delivery carriers, the lack of straightforward methods for intracellular delivery quantification limits further development in this area. Herein, we designed a simple and versatile bioorthogonal luminescent reaction (BioLure assay) to analyze intracellular delivery. Our results suggest that BioLure can be used to estimate the amount of intracellularly delivered molecules after electroporation, and the estimation by BioLure is in good correlation with the results from complementary methods. Furthermore, we used BioLure assay to correlate the intracellularly-delivered RNase A amount with its tumoricidal activity. Overall, BioLure is a versatile tool for understanding the intracellular delivery process on live cells, and establishing the link between the cytosolic concentration of intracellularly-delivered biotherapeutics and their therapeutic efficacy. Efficient intracellular delivery is crucial for biotherapeutics to achieve their efficacy, however, evaluation of delivery efficiency remains challenging. Here, the authors design a bioorthogonal luminescent reaction to analyze intracellular delivery, showing the application in electroporation-mediated protein delivery.
{"title":"Quantitative analysis of electroporation-mediated intracellular delivery via bioorthogonal luminescent reaction","authors":"Shiqi Wang, Mariia V. Shcherbii, Sami-Pekka Hirvonen, Gudrun Silvennoinen, Mirkka Sarparanta, Hélder A. Santos","doi":"10.1038/s42004-024-01266-4","DOIUrl":"10.1038/s42004-024-01266-4","url":null,"abstract":"Efficient intracellular delivery is crucial for biotherapeutics, such as proteins, oligonucleotides, and CRISPR/Cas9 gene-editing systems, to achieve their efficacy. Despite the great efforts of developing new intracellular delivery carriers, the lack of straightforward methods for intracellular delivery quantification limits further development in this area. Herein, we designed a simple and versatile bioorthogonal luminescent reaction (BioLure assay) to analyze intracellular delivery. Our results suggest that BioLure can be used to estimate the amount of intracellularly delivered molecules after electroporation, and the estimation by BioLure is in good correlation with the results from complementary methods. Furthermore, we used BioLure assay to correlate the intracellularly-delivered RNase A amount with its tumoricidal activity. Overall, BioLure is a versatile tool for understanding the intracellular delivery process on live cells, and establishing the link between the cytosolic concentration of intracellularly-delivered biotherapeutics and their therapeutic efficacy. Efficient intracellular delivery is crucial for biotherapeutics to achieve their efficacy, however, evaluation of delivery efficiency remains challenging. Here, the authors design a bioorthogonal luminescent reaction to analyze intracellular delivery, showing the application in electroporation-mediated protein delivery.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-12"},"PeriodicalIF":5.9,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01266-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1038/s42004-024-01271-7
Yuri Hong, Surim Yoo, Jihoon Han, Junseong Kim, Yongjin Lee, YongSeok Jho, Youn Soo Kim, Dong Soo Hwang
Complex coacervation plays an important role in various fields. Here, the influences of the backbone chemistry and ionic functional groups of five pairs of oppositely charged polyelectrolytes on complex coacervation were investigated. These pairs include synthetic polymers with aliphatic hydrocarbon backbones, peptides with amide bonds, and carbohydrates with glycosidic linkages. Despite sharing identical charged groups, specific pairs displayed distinct liquid/liquid and liquid/solid phase separations depending on the polyelectrolyte mixing ratio, buffer, and ionic strength. The coacervate phase boundary broadened in the orders: glycosidic linkages > amide backbone > aliphatic hydrocarbon backbone, and Tris-phosphate > Tris-acetate > Tris-chloride buffers. Coacervates prepared from polyelectrolytes with lower solubilities in water resisted disassembly at high salt concentrations, and their merge rate was slow. These observations suggest that the hydrophobic segments in polyelectrolytes interfere with the formation of complex coacervates; however, following coacervate formation, the hydrophobic segments render the coacervates stable and elastic. Complex coacervation is propelled by the electrostatic association between oppositely charged polyelectrolytes, but the factors that drive complex coacervation have yet to be fully understood. Here, the authors investigate the influence of the backbone chemistry and ionic functional groups of five pairs of oppositely charged polyelectrolytes on complex coacervation.
{"title":"Influence of the backbone chemistry and ionic functional groups of five pairs of oppositely charged polyelectrolytes on complex coacervation","authors":"Yuri Hong, Surim Yoo, Jihoon Han, Junseong Kim, Yongjin Lee, YongSeok Jho, Youn Soo Kim, Dong Soo Hwang","doi":"10.1038/s42004-024-01271-7","DOIUrl":"10.1038/s42004-024-01271-7","url":null,"abstract":"Complex coacervation plays an important role in various fields. Here, the influences of the backbone chemistry and ionic functional groups of five pairs of oppositely charged polyelectrolytes on complex coacervation were investigated. These pairs include synthetic polymers with aliphatic hydrocarbon backbones, peptides with amide bonds, and carbohydrates with glycosidic linkages. Despite sharing identical charged groups, specific pairs displayed distinct liquid/liquid and liquid/solid phase separations depending on the polyelectrolyte mixing ratio, buffer, and ionic strength. The coacervate phase boundary broadened in the orders: glycosidic linkages > amide backbone > aliphatic hydrocarbon backbone, and Tris-phosphate > Tris-acetate > Tris-chloride buffers. Coacervates prepared from polyelectrolytes with lower solubilities in water resisted disassembly at high salt concentrations, and their merge rate was slow. These observations suggest that the hydrophobic segments in polyelectrolytes interfere with the formation of complex coacervates; however, following coacervate formation, the hydrophobic segments render the coacervates stable and elastic. Complex coacervation is propelled by the electrostatic association between oppositely charged polyelectrolytes, but the factors that drive complex coacervation have yet to be fully understood. Here, the authors investigate the influence of the backbone chemistry and ionic functional groups of five pairs of oppositely charged polyelectrolytes on complex coacervation.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-10"},"PeriodicalIF":5.9,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01271-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-13DOI: 10.1038/s42004-024-01256-6
Zdeněk Kejík, Jan Hajduch, Nikita Abramenko, Frédéric Vellieux, Kateřina Veselá, Jindřiška Leischner Fialová, Kateřina Petrláková, Kateřina Kučnirová, Robert Kaplánek, Ameneh Tatar, Markéta Skaličková, Michal Masařík, Petr Babula, Petr Dytrych, David Hoskovec, Pavel Martásek, Milan Jakubek
Mitochondrial dysregulation plays a significant role in the carcinogenesis. On the other hand, its destabilization strongly represses the viability and metastatic potential of cancer cells. Photodynamic and photothermal therapies (PDT and PTT) target mitochondria effectively, providing innovative and non-invasive anticancer therapeutic modalities. Cyanine dyes, with strong mitochondrial selectivity, show significant potential in enhancing PDT and PTT. The potential and limitations of cyanine dyes for mitochondrial PDT and PTT are discussed, along with their applications in combination therapies, theranostic techniques, and optimal delivery systems. Additionally, novel approaches for sonodynamic therapy using photoactive cyanine dyes are presented, highlighting advances in cancer treatment. Photodynamic and photothermal therapies (PDT and PTT) target mitochondria effectively, providing innovative and non-invasive anticancer therapeutic modalities. Here, the authors summarize the promise and limitations of cyanine dyes in enhancing mitochondrial PDT and PTT in cancer treatment.
线粒体失调在致癌过程中起着重要作用。另一方面,线粒体的不稳定性会严重抑制癌细胞的生存能力和转移潜力。光动力疗法和光热疗法(PDT 和 PTT)可有效靶向线粒体,提供创新的非侵入性抗癌治疗模式。具有线粒体强选择性的氰基染料在增强 PDT 和 PTT 方面显示出巨大的潜力。本文讨论了氰基染料在线粒体透射光治疗和线粒体穿刺治疗中的潜力和局限性,以及它们在联合疗法、治疗技术和最佳给药系统中的应用。此外,还介绍了使用光活性氰基染料进行声动力疗法的新方法,突显了癌症治疗的进展。
{"title":"Cyanine dyes in the mitochondria-targeting photodynamic and photothermal therapy","authors":"Zdeněk Kejík, Jan Hajduch, Nikita Abramenko, Frédéric Vellieux, Kateřina Veselá, Jindřiška Leischner Fialová, Kateřina Petrláková, Kateřina Kučnirová, Robert Kaplánek, Ameneh Tatar, Markéta Skaličková, Michal Masařík, Petr Babula, Petr Dytrych, David Hoskovec, Pavel Martásek, Milan Jakubek","doi":"10.1038/s42004-024-01256-6","DOIUrl":"10.1038/s42004-024-01256-6","url":null,"abstract":"Mitochondrial dysregulation plays a significant role in the carcinogenesis. On the other hand, its destabilization strongly represses the viability and metastatic potential of cancer cells. Photodynamic and photothermal therapies (PDT and PTT) target mitochondria effectively, providing innovative and non-invasive anticancer therapeutic modalities. Cyanine dyes, with strong mitochondrial selectivity, show significant potential in enhancing PDT and PTT. The potential and limitations of cyanine dyes for mitochondrial PDT and PTT are discussed, along with their applications in combination therapies, theranostic techniques, and optimal delivery systems. Additionally, novel approaches for sonodynamic therapy using photoactive cyanine dyes are presented, highlighting advances in cancer treatment. Photodynamic and photothermal therapies (PDT and PTT) target mitochondria effectively, providing innovative and non-invasive anticancer therapeutic modalities. Here, the authors summarize the promise and limitations of cyanine dyes in enhancing mitochondrial PDT and PTT in cancer treatment.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-39"},"PeriodicalIF":5.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11322665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-13DOI: 10.1038/s42004-024-01262-8
Markel Martínez-Carranza, Jana Škerlová, Pyung-Gang Lee, Jie Zhang, Ajda Krč, Abhishek Sirohiwal, Dave Burgin, Mark Elliott, Jules Philippe, Sarah Donald, Fraser Hornby, Linda Henriksson, Geoffrey Masuyer, Ville R. I. Kaila, Matthew Beard, Min Dong, Pål Stenmark
Botulinum neurotoxins (BoNTs) are the most potent toxins known and are used to treat an increasing number of medical disorders. All BoNTs are naturally co-expressed with a protective partner protein (NTNH) with which they form a 300 kDa complex, to resist acidic and proteolytic attack from the digestive tract. We have previously identified a new botulinum neurotoxin serotype, BoNT/X, that has unique and therapeutically attractive properties. We present the cryo-EM structure of the BoNT/X-NTNH/X complex and the crystal structure of the isolated NTNH protein. Unexpectedly, the BoNT/X complex is stable and protease-resistant at both neutral and acidic pH and disassembles only in alkaline conditions. Using the stabilizing effect of NTNH, we isolated BoNT/X and showed that it has very low potency both in vitro and in vivo. Given the high catalytic activity and translocation efficacy of BoNT/X, low activity of the full toxin is likely due to the receptor-binding domain, which presents very weak ganglioside binding and exposed hydrophobic surfaces. Botulinum neurotoxins (BoNTs) are a family of protein toxins produced by clostridial bacteria that cause muscle paralysis, and exhibit structural and functional diversity within the BoNTs family. Here, the authors report the cryo-EM structure complex of a newly identified serotype BoNT/X with their partner protein NTNH/X and reveal the complex’s pH-dependent stability and receptor-binding properties.
{"title":"Activity of botulinum neurotoxin X and its structure when shielded by a non-toxic non-hemagglutinin protein","authors":"Markel Martínez-Carranza, Jana Škerlová, Pyung-Gang Lee, Jie Zhang, Ajda Krč, Abhishek Sirohiwal, Dave Burgin, Mark Elliott, Jules Philippe, Sarah Donald, Fraser Hornby, Linda Henriksson, Geoffrey Masuyer, Ville R. I. Kaila, Matthew Beard, Min Dong, Pål Stenmark","doi":"10.1038/s42004-024-01262-8","DOIUrl":"10.1038/s42004-024-01262-8","url":null,"abstract":"Botulinum neurotoxins (BoNTs) are the most potent toxins known and are used to treat an increasing number of medical disorders. All BoNTs are naturally co-expressed with a protective partner protein (NTNH) with which they form a 300 kDa complex, to resist acidic and proteolytic attack from the digestive tract. We have previously identified a new botulinum neurotoxin serotype, BoNT/X, that has unique and therapeutically attractive properties. We present the cryo-EM structure of the BoNT/X-NTNH/X complex and the crystal structure of the isolated NTNH protein. Unexpectedly, the BoNT/X complex is stable and protease-resistant at both neutral and acidic pH and disassembles only in alkaline conditions. Using the stabilizing effect of NTNH, we isolated BoNT/X and showed that it has very low potency both in vitro and in vivo. Given the high catalytic activity and translocation efficacy of BoNT/X, low activity of the full toxin is likely due to the receptor-binding domain, which presents very weak ganglioside binding and exposed hydrophobic surfaces. Botulinum neurotoxins (BoNTs) are a family of protein toxins produced by clostridial bacteria that cause muscle paralysis, and exhibit structural and functional diversity within the BoNTs family. Here, the authors report the cryo-EM structure complex of a newly identified serotype BoNT/X with their partner protein NTNH/X and reveal the complex’s pH-dependent stability and receptor-binding properties.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-15"},"PeriodicalIF":5.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01262-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-10DOI: 10.1038/s42004-024-01260-w
Deepa B. Bailmare, Boris V. Malozyomov, Abhay D. Deshmukh
Efficient charge storage is a key requirement for a range of applications, including energy storage devices and catalysis. Metal-organic frameworks are potential materials for efficient charge storage due to their self-supported three-dimensional design. MOFs are high surface area materials made up of coordination of appropriate amounts of metal ions and organic linkers, hence used in various applications. Yet, creating an effective MOF nanostructure with reduced random crystal formation continues to be a difficult task. The energy efficiency and electrochemical yield of bulk electrodes are improved in this study by demonstrating an effective technique for growing MOFs over a conducting substrate utilizing electrodeposition. An exceptionally stable asymmetric supercapacitor is created when activated carbon cloth is combined with the resulting MOF structure that was directly synthesized via an electrochemical method resulting in 97% stability over 5k cycles which is higher than conventional processes. High performance in supercapacitors is ensured by this practical approach for producing MOF electrodes, making it a suitable structure for effective charge storage. Metal-organic frameworks (MOFs) are promising charge storage materials due to their high surface area, tunable pore size, and chemical diversity, but reliable and easy syntheses of MOF conductors are needed. Here, the authors report the electrodeposition synthesis of highly conductive cobalt MOF films and their application in a supercapacitor with a power density of 480 Wkg-1 and 5k cycle stability.
{"title":"Electrodeposition of porous metal-organic frameworks for efficient charge storage","authors":"Deepa B. Bailmare, Boris V. Malozyomov, Abhay D. Deshmukh","doi":"10.1038/s42004-024-01260-w","DOIUrl":"10.1038/s42004-024-01260-w","url":null,"abstract":"Efficient charge storage is a key requirement for a range of applications, including energy storage devices and catalysis. Metal-organic frameworks are potential materials for efficient charge storage due to their self-supported three-dimensional design. MOFs are high surface area materials made up of coordination of appropriate amounts of metal ions and organic linkers, hence used in various applications. Yet, creating an effective MOF nanostructure with reduced random crystal formation continues to be a difficult task. The energy efficiency and electrochemical yield of bulk electrodes are improved in this study by demonstrating an effective technique for growing MOFs over a conducting substrate utilizing electrodeposition. An exceptionally stable asymmetric supercapacitor is created when activated carbon cloth is combined with the resulting MOF structure that was directly synthesized via an electrochemical method resulting in 97% stability over 5k cycles which is higher than conventional processes. High performance in supercapacitors is ensured by this practical approach for producing MOF electrodes, making it a suitable structure for effective charge storage. Metal-organic frameworks (MOFs) are promising charge storage materials due to their high surface area, tunable pore size, and chemical diversity, but reliable and easy syntheses of MOF conductors are needed. Here, the authors report the electrodeposition synthesis of highly conductive cobalt MOF films and their application in a supercapacitor with a power density of 480 Wkg-1 and 5k cycle stability.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-11"},"PeriodicalIF":5.9,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01260-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The oxidation of phenolic compounds is one of the most important reactions prevalent in various biological processes, often explicitly coupled with proton transfers (PTs). Quantitative descriptions and molecular-level understanding of these proton-coupled electron transfer (PCET) reactions have been challenging. This work reports a direct observation of PCET in photodetachment (PD) photoelectron spectroscopy (PES) of hydrogen-bonded phenolic (ArOH) nitrate (NO3−) complexes, in which a much slower rising edge provides a spectroscopic signature to evidence PCET. Electronic structure calculations unveil the PCET processes to be isomer-specific, occurred only in those with their HOMOs localized on ArOH, leading to charge-separated transient states ArOH•+·NO3− triggered by ionizing phenols while simultaneously promoting PT from ArOH•+ to NO3−. Importantly, this study showcases that gas-phase PD-PES is a generic means enabling to identify PCET reactions with explicit structural and binding information. The oxidation of phenolic compounds is one of the most important reactions prevalent in various biological processes, but quantitative descriptions and molecular-level understanding of these proton-coupled electron transfer (PCET) reactions have been challenging. Here, the authors use photodetachment photoelectron spectroscopy to directly observe PCET in hydrogen-bonded phenolic nitrate complexes, in which a much slower rising edge provides a spectroscopic signature to evidence PCET
{"title":"Photodetachment photoelectron spectroscopy shows isomer-specific proton-coupled electron transfer reactions in phenolic nitrate complexes","authors":"Qinqin Yuan, Ziheng Zhang, Xiangtao Kong, Zicheng Ling, Hanhui Zhang, Longjiu Cheng, Xue-Bin Wang","doi":"10.1038/s42004-024-01257-5","DOIUrl":"10.1038/s42004-024-01257-5","url":null,"abstract":"The oxidation of phenolic compounds is one of the most important reactions prevalent in various biological processes, often explicitly coupled with proton transfers (PTs). Quantitative descriptions and molecular-level understanding of these proton-coupled electron transfer (PCET) reactions have been challenging. This work reports a direct observation of PCET in photodetachment (PD) photoelectron spectroscopy (PES) of hydrogen-bonded phenolic (ArOH) nitrate (NO3−) complexes, in which a much slower rising edge provides a spectroscopic signature to evidence PCET. Electronic structure calculations unveil the PCET processes to be isomer-specific, occurred only in those with their HOMOs localized on ArOH, leading to charge-separated transient states ArOH•+·NO3− triggered by ionizing phenols while simultaneously promoting PT from ArOH•+ to NO3−. Importantly, this study showcases that gas-phase PD-PES is a generic means enabling to identify PCET reactions with explicit structural and binding information. The oxidation of phenolic compounds is one of the most important reactions prevalent in various biological processes, but quantitative descriptions and molecular-level understanding of these proton-coupled electron transfer (PCET) reactions have been challenging. Here, the authors use photodetachment photoelectron spectroscopy to directly observe PCET in hydrogen-bonded phenolic nitrate complexes, in which a much slower rising edge provides a spectroscopic signature to evidence PCET","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-9"},"PeriodicalIF":5.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1038/s42004-024-01267-3
Purbasha Nandi, Kira DeVore, Feng Wang, Shan Li, Joel D. Walker, Thanh Tung Truong, Matthew G. LaPorte, Peter Wipf, Heidi Schlager, John McCleerey, William Paquette, Rod Carlo A. Columbres, Taiping Gan, Yu-Ping Poh, Petra Fromme, Andrew J. Flint, Mark Wolf, Donna M. Huryn, Tsui-Fen Chou, Po-Lin Chiu
Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood. This study systematically investigates the structures of new triazole inhibitors bound to both wild-type and disease mutant forms of p97 and measures their effects on function. These inhibitors bind at the interface of the D1 and D2 domains of each p97 subunit, shifting surrounding helices and altering the loop structures near the C-terminal α2 G helix to modulate domain-domain communications. A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications. Human p97 ATPase, a critical drug target for neurodegenerative disorders and cancers, can be allosterically inhibited by triazole-based inhibitors. In this study, the authors investigate the structure and functions of newly designed triazole inhibitors in both wild-type and disease mutant forms of p97 to elucidate the previously unexplored inhibitory mechanisms, shedding new light on the design concept for p97 allosteric inhibitors.
人类 p97 ATPase 在各种细胞过程中起着关键作用,因此成为治疗癌症、神经疾病和传染性疾病抑制剂的靶点。在细胞模型中,三唑异构 p97 抑制剂已被证明与 ATP 竞争性抑制剂 CB-5083 的疗效相当。然而,人们对其机制还不甚了解。本研究系统地研究了与野生型和疾病突变型 p97 结合的新型三唑抑制剂的结构,并测量了它们对功能的影响。这些抑制剂结合在每个 p97 亚基的 D1 和 D2 结构域的界面上,移动周围的螺旋并改变 C 端 α2 G 螺旋附近的环结构,从而调节结构域与结构域之间的通讯。抑制剂的一个关键结构分子会影响相互作用侧链的旋转构象,从而间接调节 p97 R155H 突变体的 N 端结构域构象。抑制剂与野生型和突变型 p97 结合的不同效应为设计具有更强特异性的药物(尤其是肿瘤应用药物)提供了启示。
{"title":"Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors","authors":"Purbasha Nandi, Kira DeVore, Feng Wang, Shan Li, Joel D. Walker, Thanh Tung Truong, Matthew G. LaPorte, Peter Wipf, Heidi Schlager, John McCleerey, William Paquette, Rod Carlo A. Columbres, Taiping Gan, Yu-Ping Poh, Petra Fromme, Andrew J. Flint, Mark Wolf, Donna M. Huryn, Tsui-Fen Chou, Po-Lin Chiu","doi":"10.1038/s42004-024-01267-3","DOIUrl":"10.1038/s42004-024-01267-3","url":null,"abstract":"Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood. This study systematically investigates the structures of new triazole inhibitors bound to both wild-type and disease mutant forms of p97 and measures their effects on function. These inhibitors bind at the interface of the D1 and D2 domains of each p97 subunit, shifting surrounding helices and altering the loop structures near the C-terminal α2 G helix to modulate domain-domain communications. A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications. Human p97 ATPase, a critical drug target for neurodegenerative disorders and cancers, can be allosterically inhibited by triazole-based inhibitors. In this study, the authors investigate the structure and functions of newly designed triazole inhibitors in both wild-type and disease mutant forms of p97 to elucidate the previously unexplored inhibitory mechanisms, shedding new light on the design concept for p97 allosteric inhibitors.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-14"},"PeriodicalIF":5.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11316111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}