Nature chemical biology最新文献_第5页

Orthogonal redox control 正交氧化还原控制

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-09-24 DOI: 10.1038/s41589-024-01728-9

Lena M. Hümmler, Steffen N. Lindner

引用次数: 0

Functional profiling of serine, threonine and tyrosine sites 丝氨酸、苏氨酸和酪氨酸位点的功能分析

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-23 DOI: 10.1038/s41589-024-01731-0

Yizhou Li, Tao Xu, Huazheng Ma, Di Yue, Qiezhong Lamao, Ying Liu, Zhuo Zhou, Wensheng Wei

{"title":"Functional profiling of serine, threonine and tyrosine sites","authors":"Yizhou Li, Tao Xu, Huazheng Ma, Di Yue, Qiezhong Lamao, Ying Liu, Zhuo Zhou, Wensheng Wei","doi":"10.1038/s41589-024-01731-0","DOIUrl":"https://doi.org/10.1038/s41589-024-01731-0","url":null,"abstract":"Systematic perturbation of amino acids at endogenous loci provides diverse insights into protein function. Here, we performed a genome-wide screen to globally assess the cell fitness dependency of serine, threonine and tyrosine residues. Using an adenine base editor, we designed a whole-genome library comprising 817,089 single guide RNAs to perturb 584,337 S, T and Y sites. We identified 3,467 functional substitutions affecting cell fitness and 677 of them involving phosphorylation, including numerous phosphorylation-mediated gain-of-function substitutions that regulate phosphorylation levels of itself or downstream factors. Furthermore, our findings highlight that specific substitution types, notably serine to proline, are crucial for maintaining domain structure broadly. Lastly, we demonstrate that 309 enriched hits capable of initiating cell overproliferation might be potential cancer driver mutations. This study represents an extensive functional profiling of S, T and Y residues and provides insights into the distinctive roles of these amino acids in biological mechanisms and tumor progression.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"14 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276889","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

Where chemical biology meets physiology 化学生物学与生理学的结合

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-09-20 DOI: 10.1038/s41589-024-01739-6

Kimberly E. Beatty, Carsten Schultz

引用次数: 0

A tRNA modification with aminovaleramide facilitates AUA decoding in protein synthesis 用氨基戊酰胺修饰 tRNA 可促进蛋白质合成中的 AUA 解码

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-19 DOI: 10.1038/s41589-024-01726-x

Kenjyo Miyauchi, Satoshi Kimura, Naho Akiyama, Kazuki Inoue, Kensuke Ishiguro, Thien-Son Vu, Veerasak Srisuknimit, Kenta Koyama, Gosuke Hayashi, Akiko Soma, Asuteka Nagao, Mikako Shirouzu, Akimitsu Okamoto, Matthew K. Waldor, Tsutomu Suzuki

{"title":"A tRNA modification with aminovaleramide facilitates AUA decoding in protein synthesis","authors":"Kenjyo Miyauchi, Satoshi Kimura, Naho Akiyama, Kazuki Inoue, Kensuke Ishiguro, Thien-Son Vu, Veerasak Srisuknimit, Kenta Koyama, Gosuke Hayashi, Akiko Soma, Asuteka Nagao, Mikako Shirouzu, Akimitsu Okamoto, Matthew K. Waldor, Tsutomu Suzuki","doi":"10.1038/s41589-024-01726-x","DOIUrl":"https://doi.org/10.1038/s41589-024-01726-x","url":null,"abstract":"Modified tRNA anticodons are critical for proper mRNA translation during protein synthesis. It is generally thought that almost all bacterial tRNAsIle use a modified cytidine—lysidine (L)—at the first position (34) of the anticodon to decipher the AUA codon as isoleucine (Ile). Here we report that tRNAsIle from plant organelles and a subset of bacteria contain a new cytidine derivative, designated 2-aminovaleramididine (ava2C). Like L34, ava2C34 governs both Ile-charging ability and AUA decoding. Cryo-electron microscopy structural analyses revealed molecular details of codon recognition by ava2C34 with a specific interaction between its terminal amide group and an mRNA residue 3′-adjacent to the AUA codon. These findings reveal the evolutionary variation of an essential tRNA modification and demonstrate the molecular basis of AUA decoding mediated by a unique tRNA modification.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"23 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245854","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

Compact RNA editors with natural miniature Cas13j nucleases 带有天然微型 Cas13j 核酸酶的紧凑型 RNA 编辑器

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-19 DOI: 10.1038/s41589-024-01729-8

Guo Li, Yaxian Cheng, Jingwen Yu, Yunfei Zhu, Hongru Ma, Yuqiao Zhou, Zhongji Pu, Guanglin Zhu, Yichen Yuan, Ziyue Zhang, Xinzhi Zhou, Kairen Tian, Jianjun Qiao, Xiaoxiang Hu, Xue-xin Chen, Quanjiang Ji, Xingxu Huang, Bin Ma, Yuan Yao

{"title":"Compact RNA editors with natural miniature Cas13j nucleases","authors":"Guo Li, Yaxian Cheng, Jingwen Yu, Yunfei Zhu, Hongru Ma, Yuqiao Zhou, Zhongji Pu, Guanglin Zhu, Yichen Yuan, Ziyue Zhang, Xinzhi Zhou, Kairen Tian, Jianjun Qiao, Xiaoxiang Hu, Xue-xin Chen, Quanjiang Ji, Xingxu Huang, Bin Ma, Yuan Yao","doi":"10.1038/s41589-024-01729-8","DOIUrl":"https://doi.org/10.1038/s41589-024-01729-8","url":null,"abstract":"Clustered regularly interspaced short palindromic repeats–Cas13 effectors are used for RNA editing but the adeno-associated virus (AAV) packaging limitations because of their big sizes hinder their therapeutic application. Here we report the identification of the Cas13j family, with LepCas13j (529 aa) and ChiCas13j (424 aa) being the smallest and most highly efficient variants for RNA interference. The miniaturized Cas13j proteins enable the development of compact RNA base editors. Chi-RESCUE-S, by fusing dChiCas13j with hADAR2dd, demonstrates high efficiency and specificity in A-to-G and C-to-U conversions. Importantly, this system is compatible with single-AAV packaging without the need for protein sequence truncation. It successfully corrected pathogenic mutations, such as APOC3D65N and SCN9AR896Q, to the wild-type forms. In addition, we developed an optimized system, Chi-RESCUE-S-mini3, which pioneered efficient in vivo C-to-U RNA editing of PCSK9 in mice through single-AAV delivery, resulting in reduced total cholesterol levels. These results highlight the potential of Cas13j to treat human diseases.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"46 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245855","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

Beware of extreme calculated lipophilicity when designing cyclic peptides 设计环肽时要注意计算出的极端亲油性

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-09-19 DOI: 10.1038/s41589-024-01715-0

Vasanthanathan Poongavanam, Duc Duy Vo, Jan Kihlberg

引用次数: 0

An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes 利用共价探针通过旁系跳跃绘制异源细胞周期蛋白 E-CDK2 位点图

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2024-09-18 DOI: 10.1038/s41589-024-01738-7

Yuanjin Zhang, Zhonglin Liu, Marscha Hirschi, Oleg Brodsky, Eric Johnson, Sang Joon Won, Asako Nagata, Divya Bezwada, Matthew D. Petroski, Jaimeen D. Majmudar, Sherry Niessen, Todd VanArsdale, Adam M. Gilbert, Matthew M. Hayward, Al E. Stewart, Andrew R. Nager, Bruno Melillo, Benjamin F. Cravatt

{"title":"An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes","authors":"Yuanjin Zhang, Zhonglin Liu, Marscha Hirschi, Oleg Brodsky, Eric Johnson, Sang Joon Won, Asako Nagata, Divya Bezwada, Matthew D. Petroski, Jaimeen D. Majmudar, Sherry Niessen, Todd VanArsdale, Adam M. Gilbert, Matthew M. Hayward, Al E. Stewart, Andrew R. Nager, Bruno Melillo, Benjamin F. Cravatt","doi":"10.1038/s41589-024-01738-7","DOIUrl":"https://doi.org/10.1038/s41589-024-01738-7","url":null,"abstract":"More than half of the ~20,000 protein-encoding human genes have paralogs. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to subsets of paralogous proteins. Here we explore whether such covalent compound–cysteine interactions can be used to discover ligandable pockets in paralogs lacking the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we substituted the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide–CCNE1-N112C interaction into in vitro NanoBRET (bioluminescence resonance energy transfer) and in cellulo activity-based protein profiling assays capable of identifying compounds that reversibly inhibit both the N112C mutant and wild-type CCNE1:CDK2 (cyclin-dependent kinase 2) complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings, thus, show how electrophile–cysteine interactions mapped by chemical proteomics can extend the understanding of protein ligandability beyond covalent chemistry.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"98 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236856","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

Sweet RNA 甜味 RNA

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-09-18 DOI: 10.1038/s41589-024-01746-7

Yiyun Song

引用次数: 0

Anti-aggregate activity 抗聚集活性

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-09-18 DOI: 10.1038/s41589-024-01745-8

Russell Johnson

引用次数: 0

Breaking down taurine 分解牛磺酸

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2024-09-18 DOI: 10.1038/s41589-024-01747-6

Grant Miura

引用次数: 0