Nature chemical biology最新文献_第3页

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-10-22 DOI: 10.1038/s41589-024-01767-2

Majda Bratovič

引用次数: 0

Selective targeting of oncogenic hotspot mutations of the HER2 extracellular domain 选择性靶向 HER2 细胞外结构域的致癌热点突变

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-10-22 DOI: 10.1038/s41589-024-01751-w

Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide

{"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":"75 1","pages":""},"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}

引用次数: 0

Forming folate-fortified rice 形成叶酸强化大米

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-10-22 DOI: 10.1038/s41589-024-01773-4

Francesco Zamberlan

引用次数: 0

Molecular glue modulates mitochondria 分子胶调节线粒体

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-10-22 DOI: 10.1038/s41589-024-01769-0

Engi Hassaan

引用次数: 0

Studying ATP synthesis in situ 原位研究 ATP 合成

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-10-22 DOI: 10.1038/s41589-024-01768-1

Benjamin McIlwain

引用次数: 0

Predicting small-molecule partitioning 预测小分子分配

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-10-22 DOI: 10.1038/s41589-024-01774-3

Russell Johnson

引用次数: 0

Paenilamicins bind to a unique site on the ribosome to inhibit protein synthesis 苯胺类药物与核糖体上的一个独特位点结合，抑制蛋白质合成

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-10-22 DOI: 10.1038/s41589-024-01753-8

引用次数: 0

Designed with interactome-based deep learning 设计基于交互式深度学习

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-10-18 DOI: 10.1038/s41589-024-01754-7

Xueying Mao, Yanyi Chu, Dongqing Wei

引用次数: 0

Paenilamicins are context-specific translocation inhibitors of protein synthesis 苯胺类药物是蛋白质合成的特异性转运抑制剂

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-10-17 DOI: 10.1038/s41589-024-01752-9

Timm O. Koller, Max J. Berger, Martino Morici, Helge Paternoga, Timur Bulatov, Adriana Di Stasi, Tam Dang, Andi Mainz, Karoline Raulf, Caillan Crowe-McAuliffe, Marco Scocchi, Mario Mardirossian, Bertrand Beckert, Nora Vázquez-Laslop, Alexander S. Mankin, Roderich D. Süssmuth, Daniel N. Wilson

{"title":"Paenilamicins are context-specific translocation inhibitors of protein synthesis","authors":"Timm O. Koller, Max J. Berger, Martino Morici, Helge Paternoga, Timur Bulatov, Adriana Di Stasi, Tam Dang, Andi Mainz, Karoline Raulf, Caillan Crowe-McAuliffe, Marco Scocchi, Mario Mardirossian, Bertrand Beckert, Nora Vázquez-Laslop, Alexander S. Mankin, Roderich D. Süssmuth, Daniel N. Wilson","doi":"10.1038/s41589-024-01752-9","DOIUrl":"10.1038/s41589-024-01752-9","url":null,"abstract":"The paenilamicins are a group of hybrid nonribosomal peptide–polyketide compounds produced by the honey bee pathogen Paenibacillus larvae that display activity against Gram-positive pathogens, such as Staphylococcus aureus. While paenilamicins have been shown to inhibit protein synthesis, their mechanism of action has remained unclear. Here we determine structures of paenilamicin PamB2-stalled ribosomes, revealing a unique binding site on the small 30S subunit located between the A- and P-site transfer RNAs (tRNAs). In addition to providing a precise description of interactions of PamB2 with the ribosome, the structures also rationalize the resistance mechanisms used by P. larvae. We further demonstrate that PamB2 interferes with the translocation of messenger RNA and tRNAs through the ribosome during translation elongation, and that this inhibitory activity is influenced by the presence of modifications at position 37 of the A-site tRNA. Collectively, our study defines the paenilamicins as a class of context-specific translocation inhibitors. The paenilamicins are hybrid nonribosomal peptide–polyketide compounds that inhibit protein synthesis. Here the authors reveal that paenilamicins bind to a unique site on the ribosome, where they interfere with the translocation of mRNA and tRNAs during elongation.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"20 12","pages":"1691-1700"},"PeriodicalIF":12.9,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41589-024-01752-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440839","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}

引用次数: 0

Methylarginine targeting chimeras for lysosomal degradation of intracellular proteins 用于细胞内蛋白质溶酶体降解的甲基精氨酸靶向嵌合体

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-10-16 DOI: 10.1038/s41589-024-01741-y

Laurence J. Seabrook, Carolina N. Franco, Cody A. Loy, Jaida Osman, Callie Fredlender, Jan Zimak, Melissa Campos, Steven T. Nguyen, Richard L. Watson, Samantha R. Levine, Marian F. Khalil, Kaelyn Sumigray, Darci J. Trader, Lauren V. Albrecht

{"title":"Methylarginine targeting chimeras for lysosomal degradation of intracellular proteins","authors":"Laurence J. Seabrook, Carolina N. Franco, Cody A. Loy, Jaida Osman, Callie Fredlender, Jan Zimak, Melissa Campos, Steven T. Nguyen, Richard L. Watson, Samantha R. Levine, Marian F. Khalil, Kaelyn Sumigray, Darci J. Trader, Lauren V. Albrecht","doi":"10.1038/s41589-024-01741-y","DOIUrl":"10.1038/s41589-024-01741-y","url":null,"abstract":"A paradigm shift in drug development is the discovery of small molecules that harness the ubiquitin-proteasomal pathway to eliminate pathogenic proteins. Here we provide a modality for targeted protein degradation in lysosomes. We exploit an endogenous lysosomal pathway whereby protein arginine methyltransferases (PRMTs) initiate substrate degradation via arginine methylation. We developed a heterobifunctional small molecule, methylarginine targeting chimera (MrTAC), that recruits PRMT1 to a target protein for induced degradation in lysosomes. MrTAC compounds degraded substrates across cell lines, timescales and doses. MrTAC degradation required target protein methylation for subsequent lysosomal delivery via microautophagy. A library of MrTAC molecules exemplified the generality of MrTAC to degrade known targets and neo-substrates—glycogen synthase kinase 3β, MYC, bromodomain-containing protein 4 and histone deacetylase 6. MrTAC selectively degraded target proteins and drove biological loss-of-function phenotypes in survival, transcription and proliferation. Collectively, MrTAC demonstrates the utility of endogenous lysosomal proteolysis in the generation of a new class of small molecule degraders. Development of a targeted protein degradation platform, methylarginine targeting chimera (MrTAC), enables arginine methylation-driven degradation of intracellular proteins in lysosomes.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"20 12","pages":"1566-1576"},"PeriodicalIF":12.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440259","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}

引用次数: 0