Pub Date : 2024-10-23DOI: 10.1038/s41589-024-01763-6
Darryl A. Wesener, Zachary W. Beller, Megan F. Hill, Han Yuan, David B. Belanger, Cheryl Frankfater, Nicolas Terrapon, Bernard Henrissat, Dmitry A. Rodionov, Semen A. Leyn, Andrei Osterman, Johan E. T. van Hylckama Vlieg, Jeffrey I. Gordon
Synthetic glycans (SGs) containing glycosidic linkages and structures not identified in nature offer a means for deliberately altering microbial community properties. Here pools of SG oligosaccharides were generated via polymerization of monosaccharides and screened for their ability to increase saccharolytic Bacteroides in ex vivo cultures of human fecal samples. A lead SG preparation was orally administered to gnotobiotic mice harboring a consortium of 56 cultured, phylogenetically diverse human gut bacteria and fed a Western diet. The abundances of 3 of 15 Bacteroides strains increased, most prominently B. intestinalis. Underlying mechanisms were characterized by analyzing in vivo expression of the carbohydrate utilization machinery, using retrievable microscopic paramagnetic particles with bound SG oligosaccharides and assaying SG degradation by individual purified B. intestinalis glycoside hydrolases. The results reveal that SGs can selectively co-opt carbohydrate utilization machinery in different human gut Bacteroides and demonstrate a means for identifying artificial carbohydrate structures for targeted bacterial manipulation.
{"title":"In vivo manipulation of human gut Bacteroides fitness by abiotic oligosaccharides","authors":"Darryl A. Wesener, Zachary W. Beller, Megan F. Hill, Han Yuan, David B. Belanger, Cheryl Frankfater, Nicolas Terrapon, Bernard Henrissat, Dmitry A. Rodionov, Semen A. Leyn, Andrei Osterman, Johan E. T. van Hylckama Vlieg, Jeffrey I. Gordon","doi":"10.1038/s41589-024-01763-6","DOIUrl":"https://doi.org/10.1038/s41589-024-01763-6","url":null,"abstract":"<p>Synthetic glycans (SGs) containing glycosidic linkages and structures not identified in nature offer a means for deliberately altering microbial community properties. Here pools of SG oligosaccharides were generated via polymerization of monosaccharides and screened for their ability to increase saccharolytic <i>Bacteroides</i> in ex vivo cultures of human fecal samples. A lead SG preparation was orally administered to gnotobiotic mice harboring a consortium of 56 cultured, phylogenetically diverse human gut bacteria and fed a Western diet. The abundances of 3 of 15 <i>Bacteroides</i> strains increased, most prominently <i>B. intestinalis</i>. Underlying mechanisms were characterized by analyzing in vivo expression of the carbohydrate utilization machinery, using retrievable microscopic paramagnetic particles with bound SG oligosaccharides and assaying SG degradation by individual purified <i>B. intestinalis</i> glycoside hydrolases. The results reveal that SGs can selectively co-opt carbohydrate utilization machinery in different human gut <i>Bacteroides</i> and demonstrate a means for identifying artificial carbohydrate structures for targeted bacterial manipulation.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487111","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 : 2024-10-22DOI: 10.1038/s41589-024-01766-3
Irene Serrano
{"title":"Bridging the gap in protein targeting","authors":"Irene Serrano","doi":"10.1038/s41589-024-01766-3","DOIUrl":"10.1038/s41589-024-01766-3","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452518","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 : 2024-10-22DOI: 10.1038/s41589-024-01744-9
Arginine methylation acts as a signal for intracellular proteins to be degraded in lysosomes. We developed methylarginine targeting chimera (MrTAC), a chemical tool that induces proximity with protein arginine N-methyltransferase 1 (PRMT1) to trigger arginine methylation and thus targeted protein degradation in lysosomes.
{"title":"Targeting proteins to lysosomes with a chemical inducer of arginine methylation","authors":"","doi":"10.1038/s41589-024-01744-9","DOIUrl":"https://doi.org/10.1038/s41589-024-01744-9","url":null,"abstract":"Arginine methylation acts as a signal for intracellular proteins to be degraded in lysosomes. We developed methylarginine targeting chimera (MrTAC), a chemical tool that induces proximity with protein arginine N-methyltransferase 1 (PRMT1) to trigger arginine methylation and thus targeted protein degradation in lysosomes.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452655","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 : 2024-10-22DOI: 10.1038/s41589-024-01751-w
Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide
Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been identified in receptor tyrosine kinases including HER2. However, it is challenging to selectively target a point mutant, while sparing the wild-type protein. Here we developed antibodies selective to HER2 S310F and S310Y, the two most common oncogenic mutations in the HER2 ECD, via combinatorial library screening and structure-guided design. Cryogenic-electron microscopy structures of the HER2 S310F homodimer and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimics the dimerization arm of HER2 and thus inhibit HER2 dimerization. These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development.
{"title":"Selective targeting of oncogenic hotspot mutations of the HER2 extracellular domain","authors":"Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide","doi":"10.1038/s41589-024-01751-w","DOIUrl":"https://doi.org/10.1038/s41589-024-01751-w","url":null,"abstract":"<p>Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been identified in receptor tyrosine kinases including HER2. However, it is challenging to selectively target a point mutant, while sparing the wild-type protein. Here we developed antibodies selective to HER2 S310F and S310Y, the two most common oncogenic mutations in the HER2 ECD, via combinatorial library screening and structure-guided design. Cryogenic-electron microscopy structures of the HER2 S310F homodimer and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimics the dimerization arm of HER2 and thus inhibit HER2 dimerization. These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452541","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 : 2024-10-22DOI: 10.1038/s41589-024-01768-1
Benjamin McIlwain
{"title":"Studying ATP synthesis in situ","authors":"Benjamin McIlwain","doi":"10.1038/s41589-024-01768-1","DOIUrl":"10.1038/s41589-024-01768-1","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452522","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 : 2024-10-22DOI: 10.1038/s41589-024-01753-8
Cryo-electron microscopy structures of paenilamicin-stalled ribosomes showed that it has a unique ribosome-binding site located between the A- and P-site tRNAs. Additional biochemical assays demonstrated that paenilamicins inhibit protein synthesis by blocking the movement of mRNA and tRNA through the ribosome during the elongation phase.
低温电子显微镜观察到的苯胺灵滞留核糖体结构显示，它有一个独特的核糖体结合位点，位于 A 位点和 P 位点 tRNA 之间。其他生化试验表明，苯胺灵通过阻止 mRNA 和 tRNA 在延伸阶段通过核糖体的运动来抑制蛋白质的合成。
{"title":"Paenilamicins bind to a unique site on the ribosome to inhibit protein synthesis","authors":"","doi":"10.1038/s41589-024-01753-8","DOIUrl":"https://doi.org/10.1038/s41589-024-01753-8","url":null,"abstract":"Cryo-electron microscopy structures of paenilamicin-stalled ribosomes showed that it has a unique ribosome-binding site located between the A- and P-site tRNAs. Additional biochemical assays demonstrated that paenilamicins inhibit protein synthesis by blocking the movement of mRNA and tRNA through the ribosome during the elongation phase.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452523","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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