Cell Chemical Biology最新文献_第3页

Discovery of a Pseudomonas aeruginosa-specific small molecule targeting outer membrane protein OprH-LPS interaction by a multiplexed screen 通过多路筛选发现铜绿假单胞菌外膜蛋白OprH-LPS相互作用的特异性小分子

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.12.001

Bradley E. Poulsen , Thulasi Warrier , Sulyman Barkho , Josephine Bagnall , Keith P. Romano , Tiantian White , Xiao Yu , Tomohiko Kawate , Phuong H. Nguyen , Kyra Raines , Kristina Ferrara , A. Lorelei Golas , Michael FitzGerald , Andras Boeszoermenyi , Virendar Kaushik , Michael Serrano-Wu , Noam Shoresh , Deborah T. Hung

{"title":"Discovery of a Pseudomonas aeruginosa-specific small molecule targeting outer membrane protein OprH-LPS interaction by a multiplexed screen","authors":"Bradley E. Poulsen , Thulasi Warrier , Sulyman Barkho , Josephine Bagnall , Keith P. Romano , Tiantian White , Xiao Yu , Tomohiko Kawate , Phuong H. Nguyen , Kyra Raines , Kristina Ferrara , A. Lorelei Golas , Michael FitzGerald , Andras Boeszoermenyi , Virendar Kaushik , Michael Serrano-Wu , Noam Shoresh , Deborah T. Hung","doi":"10.1016/j.chembiol.2024.12.001","DOIUrl":"10.1016/j.chembiol.2024.12.001","url":null,"abstract":"<div><div>The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against <em>Pseudomonas aeruginosa</em>, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of <em>P. aeruginosa</em> combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT, a target-based, whole-cell screening strategy, to discover small molecule probes that kill <em>P. aeruginosa</em> mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a <em>P. aeruginosa</em> mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM β-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal pathogen biology.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 307-324.e15"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888682","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 widespread and ancient bacterial machinery assembles cytochrome OmcS nanowires essential for extracellular electron transfer 一种广泛而古老的细菌机器组装细胞色素OmcS纳米线，对细胞外电子转移至关重要

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.12.013

Cong Shen , Aldo I. Salazar-Morales , Wonhyeuk Jung , Joey Erwin , Yangqi Gu , Anthony Coelho , Kallol Gupta , Sibel Ebru Yalcin , Fadel A. Samatey , Nikhil S. Malvankar

{"title":"A widespread and ancient bacterial machinery assembles cytochrome OmcS nanowires essential for extracellular electron transfer","authors":"Cong Shen , Aldo I. Salazar-Morales , Wonhyeuk Jung , Joey Erwin , Yangqi Gu , Anthony Coelho , Kallol Gupta , Sibel Ebru Yalcin , Fadel A. Samatey , Nikhil S. Malvankar","doi":"10.1016/j.chembiol.2024.12.013","DOIUrl":"10.1016/j.chembiol.2024.12.013","url":null,"abstract":"<div><div>Microbial extracellular electron transfer (EET) drives various globally important environmental phenomena and has biotechnology applications. Diverse prokaryotes have been proposed to perform EET via surface-displayed “nanowires” composed of multi-heme cytochromes. However, the mechanism that enables only a few cytochromes to polymerize into nanowires is unclear. Here, we identify a highly conserved <em><u>o</u>mc<u>S</u></em>-<u>c</u>ompanion (<em>osc</em>) cluster that drives the formation of cytochrome OmcS nanowires in <em>Geobacter sulfurreducens</em>. Through a combination of genetic, biochemical, and biophysical methods, we establish that prolyl isomerase-containing chaperon OscH, channel-like OscEFG, and β-propeller-like OscD are involved in the folding, secretion, and morphology maintenance of OmcS nanowires, respectively. OscH and OscG can interact with OmcS. Furthermore, overexpression of <em>oscG</em> accelerates EET by overproducing nanowires in an ATP-dependent manner. Heme loading splits OscD; Δ<em>oscD</em> accelerates cell growth, bundles nanowires into cables. Our findings establish the mechanism and prevalence of a specialized and modular assembly system for nanowires across phylogenetically diverse species and environments</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 239-254.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981366","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 genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2025.01.002

Joseph J. Smith , Taylor R. Valentino , Austin H. Ablicki , Riddhidev Banerjee , Adam R. Colligan , Debra M. Eckert , Gabrielle A. Desjardins , Katharine L. Diehl

{"title":"A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells","authors":"Joseph J. Smith , Taylor R. Valentino , Austin H. Ablicki , Riddhidev Banerjee , Adam R. Colligan , Debra M. Eckert , Gabrielle A. Desjardins , Katharine L. Diehl","doi":"10.1016/j.chembiol.2025.01.002","DOIUrl":"10.1016/j.chembiol.2025.01.002","url":null,"abstract":"<div><div>Acetyl-coenzyme A is a central metabolite that participates in many cellular pathways. Evidence suggests that acetyl-CoA metabolism is highly compartmentalized in mammalian cells. Yet methods to measure acetyl-CoA in living cells are lacking. Herein, we engineered an acetyl-CoA biosensor from the bacterial protein PanZ and circularly permuted green fluorescent protein (cpGFP). The sensor, “PancACe,” has a maximum change of ∼2-fold and a response range of ∼10 μM–2 mM acetyl-CoA. We demonstrated that the sensor has a greater than 7-fold selectivity over coenzyme A, butyryl-CoA, malonyl-CoA, and succinyl-CoA, and a 2.3-fold selectivity over propionyl-CoA. We expressed the sensor in <em>E. coli</em> and showed that it enables detection of rapid changes in acetyl-CoA levels. By localizing the sensor to either the cytoplasm, nucleus, or mitochondria in human cells, we showed that it enables subcellular detection of changes in acetyl-CoA levels, the magnitudes of which agreed with an orthogonal PicoProbe assay.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 325-337.e10"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044669","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

An oral tricyclic STING agonist suppresses tumor growth through remodeling of the immune microenvironment

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2025.01.004

Hong-Yi Zhao , Zhongwei Liu , Jinsong Tao , Shuai Mao , Meilin Wang , Miao He , Bo Wen , Wei Gao , Duxin Sun

{"title":"An oral tricyclic STING agonist suppresses tumor growth through remodeling of the immune microenvironment","authors":"Hong-Yi Zhao , Zhongwei Liu , Jinsong Tao , Shuai Mao , Meilin Wang , Miao He , Bo Wen , Wei Gao , Duxin Sun","doi":"10.1016/j.chembiol.2025.01.004","DOIUrl":"10.1016/j.chembiol.2025.01.004","url":null,"abstract":"<div><div>Stimulator of interferon genes (STING) agonists could overcome immunosuppressive microenvironment to improve cancer immunotherapy. However, it is challenging to develop oral STING agonists to achieve systemic immunity. In this study, we discovered ZSA-51 as a potent oral STING agonist with distinct benzo[4,5]thieno[2,3-<em>c</em>]pyrrole-1,3-dione scaffold through tricyclic scaffold screening. ZSA-51, as a prodrug, exhibited nanomolar <em>in vitro</em> STING activation activity and potent <em>in vivo</em> antitumor efficacy in both colon and pancreatic cancer models. The specificity of ZSA-51 in activating STING was confirmed using STING knockout cells and a structurally similar but negative control compound. Moreover, ZSA-51 demonstrated superior oral pharmacokinetic (PK) properties with low toxicity. Importantly, ZSA-51 remodeled immune microenvironment both in tumor and lymph node. Our data suggest that ZSA-51 is a potent oral STING agonist with robust anticancer efficacy, superior PK properties, and low toxicity, holding potential for future development for cancer immunotherapy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 280-290.e14"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077214","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

A PROTAC degrader suppresses oncogenic functions of PTK6, inducing apoptosis of breast cancer cells 一种 PROTAC 降解剂可抑制 PTK6 的致癌功能，诱导乳腺癌细胞凋亡

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.10.008

Criseyda Martinez , Yan Xiong , Alison Bartkowski , Ibuki Harada , Xiaoxiao Ren , Jessica Byerly , Elisa Port , Jian Jin , Hanna Irie

{"title":"A PROTAC degrader suppresses oncogenic functions of PTK6, inducing apoptosis of breast cancer cells","authors":"Criseyda Martinez , Yan Xiong , Alison Bartkowski , Ibuki Harada , Xiaoxiao Ren , Jessica Byerly , Elisa Port , Jian Jin , Hanna Irie","doi":"10.1016/j.chembiol.2024.10.008","DOIUrl":"10.1016/j.chembiol.2024.10.008","url":null,"abstract":"<div><div>Protein tyrosine kinase 6 (PTK6), a non-receptor tyrosine kinase, is an oncogenic driver in many tumor types. However, agents that therapeutically target PTK6 are lacking. Although several PTK6 kinase inhibitors have been developed, none have been clinically translated, which may be due to kinase-independent functions that compromise their efficacy. PTK6 kinase inhibitor treatment phenocopies some, but not all effects of PTK6 downregulation. PTK6 downregulation inhibits growth of breast cancer cells, but treatment with PTK6 kinase inhibitor does not. To chemically downregulate PTK6, we designed a PROTAC, MS105, which potently and specifically degrades PTK6. Treatment with MS105, but not PTK6 kinase inhibitor, inhibits growth and induces apoptosis of breast cancer cells, phenocopying the effects of PTK6 (short hairpin RNA) shRNA/CRISPR. In contrast, both MS105 and PTK6 kinase inhibitor effectively inhibit breast cancer cell migration, supporting the differing kinase dependencies of PTK6’s oncogenic functions. Our studies support PTK6 degraders as a preferred approach to targeting PTK6 in cancer.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 255-266.e8"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601055","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

SynPull: An advanced method for studying neurodegeneration-related aggregates in synaptosomes using super-resolution microscopy

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2025.01.001

Shekhar Kedia , Emre Fertan , Yunzhao Wu , Yu P. Zhang , Georg Meisl , Jeff Y.L. Lam , Frances K. Wiseman , William A. McEwan , Annelies Quaegebeur , Maria Grazia Spillantini , John S.H. Danial , David Klenerman

{"title":"SynPull: An advanced method for studying neurodegeneration-related aggregates in synaptosomes using super-resolution microscopy","authors":"Shekhar Kedia , Emre Fertan , Yunzhao Wu , Yu P. Zhang , Georg Meisl , Jeff Y.L. Lam , Frances K. Wiseman , William A. McEwan , Annelies Quaegebeur , Maria Grazia Spillantini , John S.H. Danial , David Klenerman","doi":"10.1016/j.chembiol.2025.01.001","DOIUrl":"10.1016/j.chembiol.2025.01.001","url":null,"abstract":"<div><div>Synaptic dysfunction is a primary hallmark of both Alzheimer’s and Parkinson’s disease, leading to cognitive and behavioral decline. While alpha-synuclein, beta-amyloid, and tau are involved in the physiological functioning of synapses, their pathological aggregation has been linked to synaptopathology. The methodology for studying the small-soluble protein aggregates formed by these proteins is limited. Here we describe SynPull, a method combining single-molecule pull-down, super-resolution microscopy, and advanced computational analyses to characterize the protein aggregates in human and mouse synaptosomes. We show that AT8-positive tau aggregates are the predominant aggregate type in synaptosomes from postmortem Alzheimer’s disease brain, although the aggregate size does not change in disease. Meanwhile, the relatively smaller amount of alpha-synuclein and beta-amyloid aggregates found in the synapses are larger than the extra-synaptic ones. Collectively, these results show the utility of SynPull to study pathological aggregates in neurodegeneration, elucidating the disease mechanisms causing synaptic dysfunction.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 338-351.e4"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027103","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

An engineered cereblon optimized for high-throughput screening and molecular glue discovery 为高通量筛选和分子胶发现而优化的工程脑龙

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.11.002

Henry J. Bailey , Jonathan Eisert , Rubina Kazi , Jan Gerhartz , Dominika Ewa Pieńkowska , Ina Dressel , Joshua Vollrath , Ivan Kondratov , Tetiana Matviyuk , Nataliya Tolmachova , Varun Jayeshkumar Shah , Giulio Giuliani , Thorsten Mosler , Thomas M. Geiger , Ana M. Esteves , Sandra P. Santos , Raquel L. Sousa , Tiago M. Bandeiras , Eva-Maria Leibrock , Ulrike Bauer , Ivan Dikic

{"title":"An engineered cereblon optimized for high-throughput screening and molecular glue discovery","authors":"Henry J. Bailey , Jonathan Eisert , Rubina Kazi , Jan Gerhartz , Dominika Ewa Pieńkowska , Ina Dressel , Joshua Vollrath , Ivan Kondratov , Tetiana Matviyuk , Nataliya Tolmachova , Varun Jayeshkumar Shah , Giulio Giuliani , Thorsten Mosler , Thomas M. Geiger , Ana M. Esteves , Sandra P. Santos , Raquel L. Sousa , Tiago M. Bandeiras , Eva-Maria Leibrock , Ulrike Bauer , Ivan Dikic","doi":"10.1016/j.chembiol.2024.11.002","DOIUrl":"10.1016/j.chembiol.2024.11.002","url":null,"abstract":"<div><div>The majority of clinical degraders utilize an immunomodulatory imide drug (IMiD)-based derivative that directs their target to the E3 ligase receptor cereblon (CRBN); however, identification of IMiD molecular glue substrates has remained underexplored. To tackle this, we design human CRBN constructs, which retain all features for ternary complex formation, while allowing generation of homogenous and cost-efficient expression in <em>E. coli</em>. Extensive profiling of the construct shows it to be the “best of both worlds” in terms of binding activity and ease of production. We next designed the “Enamine focused IMiD library” and demonstrated applicability of the construct to high-throughput screening, identifying binders with high potency, ligand efficiency, and specificity. Finally, we adapt our construct for proof of principle glue screening approaches enabling IMiD cellular interactome determination. Coupled with our IMiD binding landscape the methods described here should serve as valuable tools to assist discovery of next generation CRBN glues.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 363-376.e10"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718728","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

Biogenesis and roles of tRNA queuosine modification and its glycosylated derivatives in human health and diseases tRNA队列苷修饰及其糖基化衍生物在人类健康和疾病中的生物发生和作用

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.11.004

Tsutomu Suzuki , Atsuya Ogizawa , Kensuke Ishiguro , Asuteka Nagao

引用次数: 0

Next steps for targeted protein degradation 定向降解蛋白质的下一步行动

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.10.004

Mackenzie W. Krone , Craig M. Crews

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Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation 靶向选择性PCK1和PGC-1α赖氨酸乙酰化的小分子通过增加乳酸氧化引起抗糖尿病作用

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2025.01.005

Beste Mutlu, Kfir Sharabi, Jee Hyung Sohn, Bo Yuan, Pedro Latorre-Muro, Xin Qin, Jin-Seon Yook, Hua Lin, Deyang Yu, João Paulo G. Camporez, Shingo Kajimura, Gerald I. Shulman, Sheng Hui, Theodore M. Kamenecka, Patrick R. Griffin, Pere Puigserver

引用次数: 0