Nature chemical biology最新文献_第10页

Artificial metalloenzyme assembly in cellular compartments for enhanced catalysis 用于增强催化作用的细胞室人工金属酶组装

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-08 DOI: 10.1038/s41589-024-01819-7

Tong Wu, Xianhui Chen, Yating Fei, Guopu Huang, Yingjiao Deng, Yingjie Wang, Anming Yang, Zhiyong Chen, N. Gabriel Lemcoff, Xinxin Feng, Yugang Bai

{"title":"Artificial metalloenzyme assembly in cellular compartments for enhanced catalysis","authors":"Tong Wu, Xianhui Chen, Yating Fei, Guopu Huang, Yingjiao Deng, Yingjie Wang, Anming Yang, Zhiyong Chen, N. Gabriel Lemcoff, Xinxin Feng, Yugang Bai","doi":"10.1038/s41589-024-01819-7","DOIUrl":"https://doi.org/10.1038/s41589-024-01819-7","url":null,"abstract":"Artificial metalloenzymes (ArMs) integrated within whole cells have emerged as promising catalysts; however, their sensitivity to metal centers remains a systematic challenge, resulting in diminished activity and turnover. Here we address this issue by inducing in cellulo liquid–liquid phase separation through a self-labeling fusion protein, HaloTag–SNAPTag. This strategy creates membraneless, isolated liquid condensates within Escherichia coli as protective compartments for the assembly of ArMs using the same fusion protein. The approach allows for high ArM loading and stabilization by localizing the ArMs within the phase-separated regions. Consequently, the performance of ArM-based whole-cell catalysts is improved, with a demonstrated turnover per cell of up to 7.1 × 109 for the olefin metathesis reaction. Furthermore, we apply this to an engineered E. coli system in live mice, where host bacterial cells confine the metal catalytic species, and in a mouse colorectal cancer model, where ArM-containing whole-cell catalysts mediate concurrent reactions to activate prodrugs.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"36 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936393","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

Mechanisms of metabolism-coupled protein modifications 代谢偶联蛋白修饰的机制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-07 DOI: 10.1038/s41589-024-01805-z

Bingsen Zhang, Frank C. Schroeder

引用次数: 0

Molecular mechanisms of inverse agonism via κ-opioid receptor–G protein complexes κ-阿片受体- g蛋白复合物拮抗作用的分子机制

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-07 DOI: 10.1038/s41589-024-01812-0

Aaliyah S. Tyson, Saif Khan, Zenia Motiwala, Gye Won Han, Zixin Zhang, Mohsen Ranjbar, Daniel Styrpejko, Nokomis Ramos-Gonzalez, Stone Woo, Kelly Villers, Delainey Landaker, Terry Kenakin, Ryan Shenvi, Susruta Majumdar, Cornelius Gati

{"title":"Molecular mechanisms of inverse agonism via κ-opioid receptor–G protein complexes","authors":"Aaliyah S. Tyson, Saif Khan, Zenia Motiwala, Gye Won Han, Zixin Zhang, Mohsen Ranjbar, Daniel Styrpejko, Nokomis Ramos-Gonzalez, Stone Woo, Kelly Villers, Delainey Landaker, Terry Kenakin, Ryan Shenvi, Susruta Majumdar, Cornelius Gati","doi":"10.1038/s41589-024-01812-0","DOIUrl":"https://doi.org/10.1038/s41589-024-01812-0","url":null,"abstract":"Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor–G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist. The pharmacological impact of agonist-free receptor–G protein complexes is poorly understood. Here we present biochemical evidence that certain κ-opioid receptor (KOR) inverse agonists can act via KOR–Gi protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR–Gi protein complexes with three inverse agonists: JDTic, norBNI and GB18, corresponding to structures of inverse agonist-bound GPCR–G protein complexes. Remarkably, the orthosteric binding pocket resembles the G protein-free ‘inactive’ receptor conformation, while the receptor remains coupled to the G protein. In summary, our work challenges the canonical model of receptor antagonism and offers crucial insights into GPCR pharmacology.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"203 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934760","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

FUT10 and FUT11 are protein O-fucosyltransferases that modify protein EMI domains FUT10和FUT11是蛋白O-聚焦转移酶，可修饰蛋白EMI结构域

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-07 DOI: 10.1038/s41589-024-01815-x

Huilin Hao, Youxi Yuan, Atsuko Ito, Benjamin M. Eberand, Harry Tjondro, Michelle Cielesh, Nicholas Norris, Cesar L. Moreno, Joshua W. C. Maxwell, G. Gregory Neely, Richard J. Payne, Melkam A. Kebede, Ramona J. Bieber Urbauer, Freda H. Passam, Mark Larance, Robert S. Haltiwanger

{"title":"FUT10 and FUT11 are protein O-fucosyltransferases that modify protein EMI domains","authors":"Huilin Hao, Youxi Yuan, Atsuko Ito, Benjamin M. Eberand, Harry Tjondro, Michelle Cielesh, Nicholas Norris, Cesar L. Moreno, Joshua W. C. Maxwell, G. Gregory Neely, Richard J. Payne, Melkam A. Kebede, Ramona J. Bieber Urbauer, Freda H. Passam, Mark Larance, Robert S. Haltiwanger","doi":"10.1038/s41589-024-01815-x","DOIUrl":"10.1038/s41589-024-01815-x","url":null,"abstract":"O-Fucosylation plays crucial roles in various essential biological events. Alongside the well-established O-fucosylation of epidermal growth factor-like repeats by protein O-fucosyltransferase 1 (POFUT1) and thrombospondin type 1 repeats by POFUT2, we recently identified a type of O-fucosylation on the elastin microfibril interface (EMI) domain of Multimerin-1 (MMRN1). Here, using AlphaFold2 screens, co-immunoprecipitation, enzymatic assays combined with mass spectrometric analysis and CRISPR–Cas9 knockouts, we demonstrate that FUT10 and FUT11, originally annotated in UniProt as α1,3-fucosyltransferases, are actually POFUTs responsible for modifying EMI domains; thus, we renamed them as POFUT3 and POFUT4, respectively. Like POFUT1/2, POFUT3/4 function in the endoplasmic reticulum, require folded domain structures for modification and participate in a non-canonical endoplasmic reticulum quality control pathway for EMI domain-containing protein secretion. This finding expands the O-fucosylation repertoire and provides an entry point for further exploration in this emerging field of O-fucosylation. FUT10 and FUT11, originally annotated as α1,3-fucosyltransferases, are actually protein O-fucosyltransferases participating in a non-canonical ER quality control pathway for EMI domain-containing protein secretion.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 4","pages":"598-610"},"PeriodicalIF":12.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41589-024-01815-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934759","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

E2–Ub-R74G strategy reveals E2-specific ubiquitin conjugation profiles in live cells E2-Ub-R74G策略揭示了活细胞中e2特异性泛素偶联谱

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-06 DOI: 10.1038/s41589-024-01809-9

Siqi Shen, Hang Yin

{"title":"E2–Ub-R74G strategy reveals E2-specific ubiquitin conjugation profiles in live cells","authors":"Siqi Shen, Hang Yin","doi":"10.1038/s41589-024-01809-9","DOIUrl":"https://doi.org/10.1038/s41589-024-01809-9","url":null,"abstract":"The E2 ubiquitin (Ub)-conjugating enzyme primarily determines Ub conjugation as Ub-isopeptide (lysine), Ub-oxyester (serine/threonine) or Ub-thioester (cysteine). However, E2-specific Ub conjugation profiles within cells remain elusive. Here we developed the fusion E2–Ub-R74G profiling (FUSEP) strategy to access E2-specific Ub conjugation profiles in cells with amino acid resolution. The probe-specific leucine-glycine-glycine-glycine-modified Ub remnant enables systematic studies of non-lysine Ub conjugation and provides site-specific information. Multiple E2 enzymes were found to be involved in non-lysine ubiquitination. Profiling with UBE2D3–Ub-R74G probes identified a post-translational modification, tyrosine ubiquitination, in human Cullin-1, a scaffold protein for Cullin-RING E3 Ub ligases. This modification is distinct from lysine ubiquitination. A single-pass membrane-bound E3 ligase, RNF149, was identified to pair with UBE2D3 to regulate pyroptosis by ubiquitinating apoptosis-associated speck-like protein ASC. The availability of this toolbox paves the way for uncovering E2-specific Ub conjugation profiles and identifying previously unknown E3 Ub ligases for potential therapeutic applications.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"27 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929677","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

Engineering covalent small molecule–RNA complexes in living cells 活细胞中共价小分子- rna复合物的工程设计

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-06 DOI: 10.1038/s41589-024-01801-3

Raphael Bereiter, Laurin Flemmich, Kamila Nykiel, Sarah Heel, Stephan Geley, Malou Hanisch, Clemens Eichler, Kathrin Breuker, Alexandra Lusser, Ronald Micura

引用次数: 0

Diary of a cell in DNA ‘chyrons’ DNA“chyrons”中的细胞日记

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-06 DOI: 10.1038/s41589-024-01814-y

Chao Chen, Harris H. Wang

引用次数: 0

Orthogonal RNA replication enables directed evolution and Darwinian adaptation in mammalian cells 正交RNA复制使定向进化和达尔文适应在哺乳动物细胞

IF 12.9 1区生物学

Nature chemical biology Pub Date : 2025-01-03 DOI: 10.1038/s41589-024-01783-2

Liang Ma, Yihan Lin

{"title":"Orthogonal RNA replication enables directed evolution and Darwinian adaptation in mammalian cells","authors":"Liang Ma, Yihan Lin","doi":"10.1038/s41589-024-01783-2","DOIUrl":"10.1038/s41589-024-01783-2","url":null,"abstract":"Directed evolution in mammalian cells offers a powerful approach for advancing synthetic biology applications. However, existing mammalian-based directed evolution methods face substantial bottlenecks, including host genome interference, small library size and uncontrolled mutagenesis. Here we engineered an orthogonal alphaviral RNA replication system to evolve RNA-based devices, enabling RNA replicase-assisted continuous evolution (REPLACE) in proliferating mammalian cells. This system generates a large, continuously diversified library of replicative RNAs through replicase-limited mode of replication and inducible mutagenesis. Using REPLACE, we engineered fluorescent proteins and transcription factors. Notably, cells equipped with REPLACE can undergo Darwinian adaptation, allowing them to evolve in response to both cell-extrinsic and cell-intrinsic challenges. Collectively, this work establishes a powerful platform for advancing mammalian synthetic biology and cell engineering applications through directed evolution. An orthogonal alphaviral RNA replication system with chemically inducible control of RNA mutagenesis enables RNA-based directed evolution in mammalian cells.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 3","pages":"451-463"},"PeriodicalIF":12.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917091","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

A rapid chemical reprogramming system to generate human pluripotent stem cells 生成人类多能干细胞的快速化学重编程系统

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-03 DOI: 10.1038/s41589-024-01799-8

Yanglu Wang, Fangqi Peng, Zhihan Yang, Lin Cheng, Jingxiao Cao, Xiaodi Fu, Huanjing He, Ruyi Cai, Weizhen Zeng, Yingshuai Dong, Guanxian Chen, Gongxin Peng, Shijia Liuyang, Guan Wang, Jinlin Wang, Rong Mu, Cheng Li, Jingyang Guan, Hongkui Deng

{"title":"A rapid chemical reprogramming system to generate human pluripotent stem cells","authors":"Yanglu Wang, Fangqi Peng, Zhihan Yang, Lin Cheng, Jingxiao Cao, Xiaodi Fu, Huanjing He, Ruyi Cai, Weizhen Zeng, Yingshuai Dong, Guanxian Chen, Gongxin Peng, Shijia Liuyang, Guan Wang, Jinlin Wang, Rong Mu, Cheng Li, Jingyang Guan, Hongkui Deng","doi":"10.1038/s41589-024-01799-8","DOIUrl":"https://doi.org/10.1038/s41589-024-01799-8","url":null,"abstract":"Chemical reprogramming enables the generation of human pluripotent stem (hCiPS) cells from somatic cells using small molecules, providing a promising strategy for regenerative medicine. However, the current method is time consuming, and some cell lines from different donors are resistant to chemical induction, limiting the utility of this approach. Here, we developed a fast reprogramming system capable of generating hCiPS cells in as few as 10 days. This accelerated method enables efficient generation of hCiPS cells with a consistent 100% success rate across 15 different donors, increasing efficiency by over 20-fold within 16 days, especially for previously resistant cells. Mechanistically, we identified KAT3A/KAT3B and KAT6A as key epigenetic obstacles; suppressing these factors facilitated the transition of somatic cells to a poised state by triggering switches in the epigenome. These results highlight the superiority of this system for generating hCiPS cells, which represents a next-generation approach for manufacturing cells for further applications.<figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"48 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917090","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

A speedy cocktail 一杯快速鸡尾酒

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2025-01-03 DOI: 10.1038/s41589-024-01804-0

Shangtao Cao, Jiekai Chen

引用次数: 0