首页 > 最新文献

Cell Discovery最新文献

英文 中文
Synthetic macrolides overcoming MLSBK-resistant pathogens. 合成大环内酯克服耐 MLSBK 病原体。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-11 DOI: 10.1038/s41421-024-00702-y
Cong-Xuan Ma, Ye Li, Wen-Tian Liu, Yun Li, Fei Zhao, Xiao-Tian Lian, Jing Ding, Si-Meng Liu, Xie-Peng Liu, Bing-Zhi Fan, Li-Yong Liu, Feng Xue, Jian Li, Jue-Ru Zhang, Zhao Xue, Xiao-Tong Pei, Jin-Zhong Lin, Jian-Hua Liang

Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSBK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSBK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSBK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSBK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.

传统的大环内酯-林可酰胺-链霉亲和素 B-酮酰胺类(MLSBK)抗生素无法应对因 rRNA 碱基 A2058 构成性甲基化或其 G2058 突变而产生的抗生素耐药性这一日益严峻的挑战,而未修饰 A2058 的存在对于传统 MLSBK 针对病原体而非人体细胞的高选择性至关重要。由于缺乏有效的作用模式,人们更加相信金黄色葡萄球菌对包括泰利霉素在内的现有大环内酯类药物仍然不敏感。在此,我们报告了一系列新型大环内酯类药物的设计和合成,其特点是将酮内酯和喹诺酮分子战略性地融合在一起。通过努力,我们发现了 MCX-219 和 MCX-190 这两种强效化合物,它们对多种可怕的病原体具有更强的抗菌效力,包括 A2058 基因变异的金黄色葡萄球菌、肺炎链球菌、化脓性链球菌,尤其是携带 A2058G 基因突变的临床肺炎支原体分离物,它们与最近在中国爆发的肺炎疫情有牵连。机理研究显示,MCX-190 的修饰喹诺酮分子在新生肽出口隧道内建立了一个独特的二级结合位点。结构-活性关系分析强调了这种二级结合的重要性,这种二级结合通过类似三明治的π-π堆积相互作用和水镁桥来维持,从而有效地与A2058甲基化核糖体而不是喹诺酮类抗生素靶向的拓扑异构酶结合。我们的发现不仅凸显了 MCX-219 和 MCX-190 作为下一代 MLSBK 抗生素的候选药物以对抗抗生素耐药性的前景,还为未来合理设计 MLSBK 类抗生素铺平了道路,为克服抗生素耐药性不断升级所带来的挑战提供了一个战略框架。
{"title":"Synthetic macrolides overcoming MLS<sub>B</sub>K-resistant pathogens.","authors":"Cong-Xuan Ma, Ye Li, Wen-Tian Liu, Yun Li, Fei Zhao, Xiao-Tian Lian, Jing Ding, Si-Meng Liu, Xie-Peng Liu, Bing-Zhi Fan, Li-Yong Liu, Feng Xue, Jian Li, Jue-Ru Zhang, Zhao Xue, Xiao-Tong Pei, Jin-Zhong Lin, Jian-Hua Liang","doi":"10.1038/s41421-024-00702-y","DOIUrl":"10.1038/s41421-024-00702-y","url":null,"abstract":"<p><p>Conventional macrolide-lincosamide-streptogramin B-ketolide (MLS<sub>B</sub>K) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLS<sub>B</sub>K in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLS<sub>B</sub>K antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLS<sub>B</sub>K antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"75"},"PeriodicalIF":13.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11239830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589679","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
Simultaneous de novo calling and phasing of genetic variants at chromosome-scale using NanoStrand-seq. 利用 NanoStrand-seq 在染色体尺度上同时进行基因变异的从头调用和分期。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-09 DOI: 10.1038/s41421-024-00694-9
Xiuzhen Bai, Zonggui Chen, Kexuan Chen, Zixin Wu, Rui Wang, Jun'e Liu, Liang Chang, Lu Wen, Fuchou Tang

The successful accomplishment of the first telomere-to-telomere human genome assembly, T2T-CHM13, marked a milestone in achieving completeness of the human reference genome. The upcoming era of genome study will focus on fully phased diploid genome assembly, with an emphasis on genetic differences between individual haplotypes. Most existing sequencing approaches only achieved localized haplotype phasing and relied on additional pedigree information for further whole-chromosome scale phasing. The short-read-based Strand-seq method is able to directly phase single nucleotide polymorphisms (SNPs) at whole-chromosome scale but falls short when it comes to phasing structural variations (SVs). To shed light on this issue, we developed a Nanopore sequencing platform-based Strand-seq approach, which we named NanoStrand-seq. This method allowed for de novo SNP calling with high precision (99.52%) and acheived a superior phasing accuracy (0.02% Hamming error rate) at whole-chromosome scale, a level of performance comparable to Strand-seq for haplotype phasing of the GM12878 genome. Importantly, we demonstrated that NanoStrand-seq can efficiently resolve the MHC locus, a highly polymorphic genomic region. Moreover, NanoStrand-seq enabled independent direct calling and phasing of deletions and insertions at whole-chromosome level; when applied to long genomic regions of SNP homozygosity, it outperformed the strategy that combined Strand-seq with bulk long-read sequencing. Finally, we showed that, like Strand-seq, NanoStrand-seq was also applicable to primary cultured cells. Together, here we provided a novel methodology that enabled interrogation of a full spectrum of haplotype-resolved SNPs and SVs at whole-chromosome scale, with broad applications for species with diploid or even potentially polypoid genomes.

第一个端粒到端粒人类基因组T2T-CHM13的成功组装标志着人类参考基因组完整性的一个里程碑。即将到来的基因组研究时代将以全期二倍体基因组组装为重点,强调个体单倍型之间的遗传差异。现有的大多数测序方法只能实现局部的单倍型分期,进一步的全染色体规模分期需要依赖额外的血统信息。基于短读数的 Strand-seq 方法能够直接对全染色体范围内的单核苷酸多态性(SNPs)进行分型,但在对结构变异(SVs)进行分型时却存在不足。为了解决这个问题,我们开发了一种基于纳米孔测序平台的Strand-seq方法,并将其命名为NanoStrand-seq。这种方法允许高精度(99.52%)的从头SNP调用,并在全染色体范围内实现了卓越的分期准确性(0.02%的汉明错误率),其性能水平与Strand-seq对GM12878基因组的单体型分期相当。重要的是,我们证明了 NanoStrand-seq 能够高效解析 MHC 基因座这一高度多态的基因组区域。此外,NanoStrand-seq 还能在全染色体水平上对缺失和插入进行独立的直接调用和分期;当应用于 SNP 同源性的长基因组区域时,它的表现优于将 Strand-seq 与批量长线程测序相结合的策略。最后,我们表明,与 Strand-seq 一样,NanoStrand-seq 也适用于原代培养细胞。总之,我们在这里提供了一种新的方法,能够在全染色体范围内对单倍型解析的 SNP 和 SV 进行全方位的检测,可广泛应用于具有二倍体甚至潜在多倍体基因组的物种。
{"title":"Simultaneous de novo calling and phasing of genetic variants at chromosome-scale using NanoStrand-seq.","authors":"Xiuzhen Bai, Zonggui Chen, Kexuan Chen, Zixin Wu, Rui Wang, Jun'e Liu, Liang Chang, Lu Wen, Fuchou Tang","doi":"10.1038/s41421-024-00694-9","DOIUrl":"10.1038/s41421-024-00694-9","url":null,"abstract":"<p><p>The successful accomplishment of the first telomere-to-telomere human genome assembly, T2T-CHM13, marked a milestone in achieving completeness of the human reference genome. The upcoming era of genome study will focus on fully phased diploid genome assembly, with an emphasis on genetic differences between individual haplotypes. Most existing sequencing approaches only achieved localized haplotype phasing and relied on additional pedigree information for further whole-chromosome scale phasing. The short-read-based Strand-seq method is able to directly phase single nucleotide polymorphisms (SNPs) at whole-chromosome scale but falls short when it comes to phasing structural variations (SVs). To shed light on this issue, we developed a Nanopore sequencing platform-based Strand-seq approach, which we named NanoStrand-seq. This method allowed for de novo SNP calling with high precision (99.52%) and acheived a superior phasing accuracy (0.02% Hamming error rate) at whole-chromosome scale, a level of performance comparable to Strand-seq for haplotype phasing of the GM12878 genome. Importantly, we demonstrated that NanoStrand-seq can efficiently resolve the MHC locus, a highly polymorphic genomic region. Moreover, NanoStrand-seq enabled independent direct calling and phasing of deletions and insertions at whole-chromosome level; when applied to long genomic regions of SNP homozygosity, it outperformed the strategy that combined Strand-seq with bulk long-read sequencing. Finally, we showed that, like Strand-seq, NanoStrand-seq was also applicable to primary cultured cells. Together, here we provided a novel methodology that enabled interrogation of a full spectrum of haplotype-resolved SNPs and SVs at whole-chromosome scale, with broad applications for species with diploid or even potentially polypoid genomes.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"74"},"PeriodicalIF":13.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11231365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558136","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
Pig blastocyst-like structure models from embryonic stem cells. 从胚胎干细胞中提取猪胚泡样结构模型。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-02 DOI: 10.1038/s41421-024-00693-w
Jinzhu Xiang, Hanning Wang, Bingbo Shi, Jiajun Li, Dong Liu, Kaipeng Wang, Zhuangfei Wang, Qiankun Min, Chengchen Zhao, Duanqing Pei

Pluripotent stem cells have the potential to generate embryo models that can recapitulate developmental processes in vitro. Large animals such as pigs may also benefit from stem-cell-based embryo models for improving breeding. Here, we report the generation of blastoids from porcine embryonic stem cells (pESCs). We first develop a culture medium 4FIXY to derive pESCs. We develop a 3D two-step differentiation strategy to generate porcine blastoids from the pESCs. The resulting blastoids exhibit similar morphology, size, cell lineage composition, and single-cell transcriptome characteristics to blastocysts. These porcine blastoids survive and expand for more than two weeks in vitro under two different culture conditions. Large animal blastoids such as those derived from pESCs may enable in vitro modeling of early embryogenesis and improve livestock species' breeding practices.

多能干细胞有可能产生胚胎模型,在体外重现发育过程。猪等大型动物也可能受益于基于干细胞的胚胎模型,从而改善育种。在此,我们报告了用猪胚胎干细胞(pESCs)生成囊胚的情况。我们首先开发了一种培养基 4FIXY,用于培育猪胚胎干细胞。我们开发了一种三维两步分化策略,用 pESCs 生成猪胚泡。生成的囊胚表现出与囊胚相似的形态、大小、细胞系组成和单细胞转录组特征。在两种不同的培养条件下,这些猪胚泡可在体外存活和扩张两周以上。大型动物囊胚(如由 pESCs 衍生的囊胚)可用于早期胚胎发生的体外建模,并改善家畜物种的育种实践。
{"title":"Pig blastocyst-like structure models from embryonic stem cells.","authors":"Jinzhu Xiang, Hanning Wang, Bingbo Shi, Jiajun Li, Dong Liu, Kaipeng Wang, Zhuangfei Wang, Qiankun Min, Chengchen Zhao, Duanqing Pei","doi":"10.1038/s41421-024-00693-w","DOIUrl":"10.1038/s41421-024-00693-w","url":null,"abstract":"<p><p>Pluripotent stem cells have the potential to generate embryo models that can recapitulate developmental processes in vitro. Large animals such as pigs may also benefit from stem-cell-based embryo models for improving breeding. Here, we report the generation of blastoids from porcine embryonic stem cells (pESCs). We first develop a culture medium 4FIXY to derive pESCs. We develop a 3D two-step differentiation strategy to generate porcine blastoids from the pESCs. The resulting blastoids exhibit similar morphology, size, cell lineage composition, and single-cell transcriptome characteristics to blastocysts. These porcine blastoids survive and expand for more than two weeks in vitro under two different culture conditions. Large animal blastoids such as those derived from pESCs may enable in vitro modeling of early embryogenesis and improve livestock species' breeding practices.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"72"},"PeriodicalIF":13.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491019","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
Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis. 成骨细胞系的承诺、分化、骨形成和稳态的细胞信号和转录调控。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-02 DOI: 10.1038/s41421-024-00689-6
Siyu Zhu, Wei Chen, Alasdair Masson, Yi-Ping Li

The initiation of osteogenesis primarily occurs as mesenchymal stem cells undergo differentiation into osteoblasts. This differentiation process plays a crucial role in bone formation and homeostasis and is regulated by two intricate processes: cell signal transduction and transcriptional gene expression. Various essential cell signaling pathways, including Wnt, BMP, TGF-β, Hedgehog, PTH, FGF, Ephrin, Notch, Hippo, and Piezo1/2, play a critical role in facilitating osteoblast differentiation, bone formation, and bone homeostasis. Key transcriptional factors in this differentiation process include Runx2, Cbfβ, Runx1, Osterix, ATF4, SATB2, and TAZ/YAP. Furthermore, a diverse array of epigenetic factors also plays critical roles in osteoblast differentiation, bone formation, and homeostasis at the transcriptional level. This review provides an overview of the latest developments and current comprehension concerning the pathways of cell signaling, regulation of hormones, and transcriptional regulation of genes involved in the commitment and differentiation of osteoblast lineage, as well as in bone formation and maintenance of homeostasis. The paper also reviews epigenetic regulation of osteoblast differentiation via mechanisms, such as histone and DNA modifications. Additionally, we summarize the latest developments in osteoblast biology spurred by recent advancements in various modern technologies and bioinformatics. By synthesizing these insights into a comprehensive understanding of osteoblast differentiation, this review provides further clarification of the mechanisms underlying osteoblast lineage commitment, differentiation, and bone formation, and highlights potential new therapeutic applications for the treatment of bone diseases.

成骨的启动主要发生在间充质干细胞分化成成骨细胞的过程中。这一分化过程在骨形成和稳态中起着至关重要的作用,并受两个复杂过程的调控:细胞信号传导和转录基因表达。各种重要的细胞信号通路,包括 Wnt、BMP、TGF-β、Hedgehog、PTH、FGF、Ephrin、Notch、Hippo 和 Piezo1/2,在促进成骨细胞分化、骨形成和骨稳态中发挥着关键作用。这一分化过程中的关键转录因子包括 Runx2、Cbfβ、Runx1、Osterix、ATF4、SATB2 和 TAZ/YAP。此外,一系列不同的表观遗传因子也在成骨细胞分化、骨形成和转录水平的平衡中发挥着关键作用。这篇综述概述了细胞信号传导途径、激素调控、参与成骨细胞系的承诺和分化的基因转录调控以及骨形成和维持稳态的最新进展和目前的理解。本文还回顾了通过组蛋白和 DNA 修饰等机制对成骨细胞分化的表观遗传调控。此外,我们还总结了成骨细胞生物学在各种现代技术和生物信息学的推动下取得的最新进展。这篇综述将这些见解综合为对成骨细胞分化的全面理解,进一步阐明了成骨细胞系承诺、分化和骨形成的内在机制,并强调了治疗骨病的潜在新疗法应用。
{"title":"Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis.","authors":"Siyu Zhu, Wei Chen, Alasdair Masson, Yi-Ping Li","doi":"10.1038/s41421-024-00689-6","DOIUrl":"10.1038/s41421-024-00689-6","url":null,"abstract":"<p><p>The initiation of osteogenesis primarily occurs as mesenchymal stem cells undergo differentiation into osteoblasts. This differentiation process plays a crucial role in bone formation and homeostasis and is regulated by two intricate processes: cell signal transduction and transcriptional gene expression. Various essential cell signaling pathways, including Wnt, BMP, TGF-β, Hedgehog, PTH, FGF, Ephrin, Notch, Hippo, and Piezo1/2, play a critical role in facilitating osteoblast differentiation, bone formation, and bone homeostasis. Key transcriptional factors in this differentiation process include Runx2, Cbfβ, Runx1, Osterix, ATF4, SATB2, and TAZ/YAP. Furthermore, a diverse array of epigenetic factors also plays critical roles in osteoblast differentiation, bone formation, and homeostasis at the transcriptional level. This review provides an overview of the latest developments and current comprehension concerning the pathways of cell signaling, regulation of hormones, and transcriptional regulation of genes involved in the commitment and differentiation of osteoblast lineage, as well as in bone formation and maintenance of homeostasis. The paper also reviews epigenetic regulation of osteoblast differentiation via mechanisms, such as histone and DNA modifications. Additionally, we summarize the latest developments in osteoblast biology spurred by recent advancements in various modern technologies and bioinformatics. By synthesizing these insights into a comprehensive understanding of osteoblast differentiation, this review provides further clarification of the mechanisms underlying osteoblast lineage commitment, differentiation, and bone formation, and highlights potential new therapeutic applications for the treatment of bone diseases.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"71"},"PeriodicalIF":13.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491018","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
Structural basis for the inhibition mechanism of LAT1-4F2hc complex by JPH203. JPH203 抑制 LAT1-4F2hc 复合物机制的结构基础。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-02 DOI: 10.1038/s41421-024-00697-6
Ziwei Hu, Renhong Yan
{"title":"Structural basis for the inhibition mechanism of LAT1-4F2hc complex by JPH203.","authors":"Ziwei Hu, Renhong Yan","doi":"10.1038/s41421-024-00697-6","DOIUrl":"10.1038/s41421-024-00697-6","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"73"},"PeriodicalIF":13.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491020","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 pan-KRAS degrader for the treatment of KRAS-mutant cancers. 用于治疗 KRAS 突变癌症的泛 KRAS 降解剂。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-28 DOI: 10.1038/s41421-024-00699-4
Jie Yang, Qiao-Li Wang, Guan-Nan Wang, Jia-Cong Ye, Zi-Qian Li, Jing-Yun Wang, Zhao-Hui Liang, Shu-Xin Li, Cong Sun, Wen-Ting Liao, Yi-Jun Gao, Jing Wang, Yong Mao, Chunjing Yu, Guo-Kai Feng, Mu-Sheng Zeng

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

KRAS 突变在多种致命癌症中非常普遍,这些突变形式的 KRAS 在推动癌症进展和产生抗药性方面发挥着至关重要的作用。虽然针对特定 KRAS 突变体的小分子药物的开发取得了进展,但不可药用突变体的存在和二次突变的出现仍给 KRAS 突变癌症的临床治疗带来了挑战。在这项研究中,我们开发了一种名为肿瘤靶向 KRAS 降解剂(TKD)的新型分子工具,它能有效靶向多种 KRAS 突变体。TKD由一个KRAS结合纳米抗体、一个选择性靶向癌细胞的细胞穿透肽和一个溶酶体结合基团组成。我们的数据显示,TKD可选择性地与癌细胞中的KRAS结合,并通过溶酶体依赖过程有效地诱导KRAS降解。在功能上,TKD能抑制肿瘤生长,且无明显副作用,并能增强PD-1抗体和西妥昔单抗的抗肿瘤作用。这项研究不仅为开发针对 "不可药用 "蛋白的药物提供了一种策略,而且揭示了 TKD 是一种治疗 KRAS 突变癌症的有前途的疗法。
{"title":"A pan-KRAS degrader for the treatment of KRAS-mutant cancers.","authors":"Jie Yang, Qiao-Li Wang, Guan-Nan Wang, Jia-Cong Ye, Zi-Qian Li, Jing-Yun Wang, Zhao-Hui Liang, Shu-Xin Li, Cong Sun, Wen-Ting Liao, Yi-Jun Gao, Jing Wang, Yong Mao, Chunjing Yu, Guo-Kai Feng, Mu-Sheng Zeng","doi":"10.1038/s41421-024-00699-4","DOIUrl":"https://doi.org/10.1038/s41421-024-00699-4","url":null,"abstract":"<p><p>KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting \"undruggable\" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"70"},"PeriodicalIF":13.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466371","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
Structural and functional insights into the helicase protein E5 of Mpox virus. 对 Mpox 病毒螺旋酶蛋白 E5 结构和功能的深入研究。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-25 DOI: 10.1038/s41421-024-00680-1
Weizhen Zhang, Yusong Liu, Mengquan Yang, Jie Yang, Zhiwei Shao, Yanqing Gao, Xinran Jiang, Ruixue Cui, Yixi Zhang, Xin Zhao, Qiyuan Shao, Chulei Cao, Huili Li, Linxi Li, Hehua Liu, Haishan Gao, Jianhua Gan

Mpox virus (MPXV) can cause mpox in humans. Due to its quick and wide spread in the past two years, mpox has turned into a significant public health concern. Helicase E5 is a multi-domain protein; its primer synthesis and DNA unwinding activity are required for genome uncoating and DNA replication of MPXV. However, the in vitro DNA unwinding activity has never been demonstrated. Here, we report the structural and biochemical studies of MPXV E5, showing that the full-length protein adopts an auto-inhibited conformation. Truncation of the N-terminus can recover the in vitro unwinding activity of E5 towards the forked DNA. Further structural analysis reveals that MPXV E5 shares a conserved mechanism in DNA unwinding and primer synthesis with the homologous proteins. These findings not only advance our understanding on the function of MPXV E5, but also provide a solid basis for the development of anti-poxvirus drugs.

痘病毒(MPXV)可导致人类感染痘。由于痘病毒在过去两年中迅速广泛传播,痘病毒已成为一个重大的公共卫生问题。螺旋酶 E5 是一种多域蛋白,其引物合成和 DNA 解旋活性是 MPXV 的基因组解衣和 DNA 复制所必需的。然而,体外 DNA 解旋活性尚未得到证实。在此,我们报告了对 MPXV E5 的结构和生化研究,结果表明全长蛋白采用了自动抑制构象。截断 N 端可以恢复 E5 对分叉 DNA 的体外解旋活性。进一步的结构分析表明,MPXV E5 与同源蛋白在 DNA 解旋和引物合成方面有着相同的机制。这些发现不仅加深了我们对 MPXV E5 功能的理解,而且为开发抗痘病毒药物提供了坚实的基础。
{"title":"Structural and functional insights into the helicase protein E5 of Mpox virus.","authors":"Weizhen Zhang, Yusong Liu, Mengquan Yang, Jie Yang, Zhiwei Shao, Yanqing Gao, Xinran Jiang, Ruixue Cui, Yixi Zhang, Xin Zhao, Qiyuan Shao, Chulei Cao, Huili Li, Linxi Li, Hehua Liu, Haishan Gao, Jianhua Gan","doi":"10.1038/s41421-024-00680-1","DOIUrl":"10.1038/s41421-024-00680-1","url":null,"abstract":"<p><p>Mpox virus (MPXV) can cause mpox in humans. Due to its quick and wide spread in the past two years, mpox has turned into a significant public health concern. Helicase E5 is a multi-domain protein; its primer synthesis and DNA unwinding activity are required for genome uncoating and DNA replication of MPXV. However, the in vitro DNA unwinding activity has never been demonstrated. Here, we report the structural and biochemical studies of MPXV E5, showing that the full-length protein adopts an auto-inhibited conformation. Truncation of the N-terminus can recover the in vitro unwinding activity of E5 towards the forked DNA. Further structural analysis reveals that MPXV E5 shares a conserved mechanism in DNA unwinding and primer synthesis with the homologous proteins. These findings not only advance our understanding on the function of MPXV E5, but also provide a solid basis for the development of anti-poxvirus drugs.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"67"},"PeriodicalIF":13.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11196578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445708","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
Molecular recognition of the atypical chemokine-like peptide GPR15L by its cognate receptor GPR15. 其同源受体 GPR15 对非典型趋化因子样肽 GPR15L 的分子识别。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-25 DOI: 10.1038/s41421-024-00698-5
Zhongyuan Zhang, You Zheng, Lu Xu, Yang Yue, Kexin Xu, Fei Li, Fei Xu
{"title":"Molecular recognition of the atypical chemokine-like peptide GPR15L by its cognate receptor GPR15.","authors":"Zhongyuan Zhang, You Zheng, Lu Xu, Yang Yue, Kexin Xu, Fei Li, Fei Xu","doi":"10.1038/s41421-024-00698-5","DOIUrl":"10.1038/s41421-024-00698-5","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"69"},"PeriodicalIF":13.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449779","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
TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling. TMC6 作为一种类似 GPCR 的受体,通过 Gαq 信号传导来感知有害热量。
IF 33.5 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-18 DOI: 10.1038/s41421-024-00678-9
Chen Zhang, Fang Tong, Bin Zhou, Mingdong He, Shuai Liu, Xiaomeng Zhou, Qiang Ma, Tianyu Feng, Wan-Jie Du, Huan Yang, Hao Xu, Lei Xiao, Zhen-Zhong Xu, Cheng Zhu, Ruiqi Wu, Yan-Qing Wang, Qingjian Han

Thermosensation is vital for the survival, propagation, and adaption of all organisms, but its mechanism is not fully understood yet. Here, we find that TMC6, a membrane protein of unknown function, is highly expressed in dorsal root ganglion (DRG) neurons and functions as a Gαq-coupled G protein-coupled receptor (GPCR)-like receptor to sense noxious heat. TMC6-deficient mice display a substantial impairment in noxious heat sensation while maintaining normal perception of cold, warmth, touch, and mechanical pain. Further studies show that TMC6 interacts with Gαq via its intracellular C-terminal region spanning Ser780 to Pro810. Specifically disrupting such interaction using polypeptide in DRG neurons, genetically ablating Gαq, or pharmacologically blocking Gαq-coupled GPCR signaling can replicate the phenotype of TMC6 deficient mice regarding noxious heat sensation. Noxious heat stimulation triggers intracellular calcium release from the endoplasmic reticulum (ER) of TMC6- but not control vector-transfected HEK293T cell, which can be significantly inhibited by blocking PLC or IP3R. Consistently, noxious heat-induced intracellular Ca2+ release from ER and action potentials of DRG neurons largely reduced when ablating TMC6 or blocking Gαq/PLC/IP3R signaling pathway as well. In summary, our findings indicate that TMC6 can directly function as a Gαq-coupled GPCR-like receptor sensing noxious heat.

热感觉对所有生物的生存、传播和适应至关重要,但其机制尚未完全清楚。在这里,我们发现 TMC6 是一种功能未知的膜蛋白,在背根神经节(DRG)神经元中高度表达,并作为一种类似 Gαq 的 G 蛋白偶联受体(GPCR)来感知有害热。缺失 TMC6 的小鼠在对冷、暖、触觉和机械痛的感知保持正常的同时,对有害热的感觉却表现出严重的障碍。进一步的研究表明,TMC6 通过跨越 Ser780 至 Pro810 的胞内 C 端区域与 Gαq 相互作用。在DRG神经元中使用多肽、基因消融Gαq或药物阻断Gαq耦合GPCR信号传导来具体破坏这种相互作用,可以复制TMC6缺失小鼠在痛热感觉方面的表型。毒性热刺激会触发细胞内钙从TMC6转染的HEK293T细胞内质网(ER)释放,而不是对照载体转染的HEK293T细胞。同样,当消融 TMC6 或阻断 Gαq/PLC/IP3R 信号通路时,有害热诱导的细胞内 Ca2+ 从 ER 的释放和 DRG 神经元的动作电位也会大大降低。总之,我们的研究结果表明,TMC6 可直接作为 Gαq 偶联的 GPCR 样受体感知有害热。
{"title":"TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling.","authors":"Chen Zhang, Fang Tong, Bin Zhou, Mingdong He, Shuai Liu, Xiaomeng Zhou, Qiang Ma, Tianyu Feng, Wan-Jie Du, Huan Yang, Hao Xu, Lei Xiao, Zhen-Zhong Xu, Cheng Zhu, Ruiqi Wu, Yan-Qing Wang, Qingjian Han","doi":"10.1038/s41421-024-00678-9","DOIUrl":"10.1038/s41421-024-00678-9","url":null,"abstract":"<p><p>Thermosensation is vital for the survival, propagation, and adaption of all organisms, but its mechanism is not fully understood yet. Here, we find that TMC6, a membrane protein of unknown function, is highly expressed in dorsal root ganglion (DRG) neurons and functions as a Gαq-coupled G protein-coupled receptor (GPCR)-like receptor to sense noxious heat. TMC6-deficient mice display a substantial impairment in noxious heat sensation while maintaining normal perception of cold, warmth, touch, and mechanical pain. Further studies show that TMC6 interacts with Gαq via its intracellular C-terminal region spanning Ser<sup>780</sup> to Pro<sup>810</sup>. Specifically disrupting such interaction using polypeptide in DRG neurons, genetically ablating Gαq, or pharmacologically blocking Gαq-coupled GPCR signaling can replicate the phenotype of TMC6 deficient mice regarding noxious heat sensation. Noxious heat stimulation triggers intracellular calcium release from the endoplasmic reticulum (ER) of TMC6- but not control vector-transfected HEK293T cell, which can be significantly inhibited by blocking PLC or IP3R. Consistently, noxious heat-induced intracellular Ca<sup>2+</sup> release from ER and action potentials of DRG neurons largely reduced when ablating TMC6 or blocking Gαq/PLC/IP3R signaling pathway as well. In summary, our findings indicate that TMC6 can directly function as a Gαq-coupled GPCR-like receptor sensing noxious heat.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"66"},"PeriodicalIF":33.5,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11183229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417914","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
Structural basis of connexin-36 gap junction channel inhibition. 连接蛋白-36 间隙连接通道抑制作用的结构基础
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-18 DOI: 10.1038/s41421-024-00691-y
Xinyue Ding, Simone Aureli, Anand Vaithia, Pia Lavriha, Dina Schuster, Basavraj Khanppnavar, Xiaodan Li, Thorsten B Blum, Paola Picotti, Francesco L Gervasio, Volodymyr M Korkhov
{"title":"Structural basis of connexin-36 gap junction channel inhibition.","authors":"Xinyue Ding, Simone Aureli, Anand Vaithia, Pia Lavriha, Dina Schuster, Basavraj Khanppnavar, Xiaodan Li, Thorsten B Blum, Paola Picotti, Francesco L Gervasio, Volodymyr M Korkhov","doi":"10.1038/s41421-024-00691-y","DOIUrl":"10.1038/s41421-024-00691-y","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"68"},"PeriodicalIF":13.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11189382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417913","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
期刊
Cell Discovery
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1