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Structure basis for sugar specificity of gustatory receptors in insects. 昆虫味觉受体糖特异性的结构基础
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-06 DOI: 10.1038/s41421-024-00716-6
Ruizhu Chen, Ran Zhang, Lu Li, Bozhan Wang, Zhiwei Gao, Fenglian Liu, Yan Chen, Yutao Tian, Baobin Li, Qingfeng Chen
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引用次数: 0
PROTAC for Bruton's tyrosine kinase degradation alleviates inflammation in autoimmune diseases. 用于布鲁顿酪氨酸激酶降解的 PROTAC 可减轻自身免疫性疾病的炎症反应。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-06 DOI: 10.1038/s41421-024-00711-x
Can Zhu, Zimo Yang, Yuxiao Zhang, Zhenjun Li, Guangchen Li, Bing Yang, Na Kang, Jingwen Wang, Yonghui Sun, Ning Ding, Yu Rao, Wanli Liu
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引用次数: 0
p72 antigenic mapping reveals a potential supersite of vulnerability for African swine fever virus. p72 抗原图谱揭示了非洲猪瘟病毒易感性的潜在超级位点。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-31 DOI: 10.1038/s41421-024-00692-x
Qi Yu, Dening Liang, Wangjun Fu, Li Zhang, Jinglin Wang, Zhenjiang Zhang, Yao Sun, Dandan Zhu, BinYang Zheng, Ling Zhu, Ye Xiang, Dongming Zhao, Xiangxi Wang
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引用次数: 0
Structural basis of antagonist selectivity in endothelin receptors. 内皮素受体拮抗剂选择性的结构基础。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-30 DOI: 10.1038/s41421-024-00705-9
Junyi Hou, Shenhui Liu, Xiaodan Zhang, Guowei Tu, Lijie Wu, Yijie Zhang, Hao Yang, Xiangcheng Li, Junlin Liu, Longquan Jiang, Qiwen Tan, Fang Bai, Zhijie Liu, Changhong Miao, Tian Hua, Zhe Luo

Endothelins and their receptors, ETA and ETB, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ETA antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ETA in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ETA antagonist, respectively. Notably, a specialized anti-ETA antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ETA and ETB, and the agonist BQ3020-bound ETB, in complex with Gq, unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ETA. Furthermore, our results suggest that ECL2 in ETA can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors.

内皮素及其受体 ETA 和 ETB 在维持血管稳态方面发挥着重要作用。以内皮素受体为治疗靶点,特别是通过 ETA 拮抗剂,已显示出治疗肺动脉高压(PAH)和其他心血管及肾脏相关疾病的疗效。在这里,我们展示了 ETA 分别与两种 PAH 药物(马基坦坦和安利生坦)以及选择性 ETA 拮抗剂齐博坦复合物的冷冻电镜结构。值得注意的是,专门的抗 ETA 抗体促进了结构的阐明。这些结构,连同 ET-1 结合 ETA 和 ETB 的活性状态结构,以及激动剂 BQ3020 结合 ETB 与 Gq 复合物的结构,揭示了内皮素受体激动剂/拮抗剂结合模式的分子基础。我们确定了赋予内皮素受体拮抗剂选择性的关键残基以及 ETA 的激活机制。此外,我们的研究结果表明,ETA 中的 ECL2 可作为抗体介导的受体拮抗作用的表位。总之,这些见解为合理设计对内皮素受体具有选择性活性的小分子药物和抗体建立了坚实的理论框架。
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引用次数: 0
Proteogenomic insights into the biology and treatment of pan-melanoma. 蛋白质基因组学对泛黑色素瘤生物学和治疗的启示。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-23 DOI: 10.1038/s41421-024-00688-7
Hang Xiang, Rongkui Luo, Yunzhi Wang, Bing Yang, Sha Xu, Wen Huang, Shaoshuai Tang, Rundong Fang, Lingli Chen, Na Zhu, Zixiang Yu, Sujie Akesu, Chuanyuan Wei, Chen Xu, Yuhong Zhou, Jianying Gu, Jianyuan Zhao, Yingyong Hou, Chen Ding

Melanoma is one of the most prevalent skin cancers, with high metastatic rates and poor prognosis. Understanding its molecular pathogenesis is crucial for improving its diagnosis and treatment. Integrated analysis of multi-omics data from 207 treatment-naïve melanomas (primary-cutaneous-melanomas (CM, n = 28), primary-acral-melanomas (AM, n = 81), primary-mucosal-melanomas (MM, n = 28), metastatic-melanomas (n = 27), and nevi (n = 43)) provides insights into melanoma biology. Multivariate analysis reveals that PRKDC amplification is a prognostic molecule for melanomas. Further proteogenomic analysis combined with functional experiments reveals that the cis-effect of PRKDC amplification may lead to tumor proliferation through the activation of DNA repair and folate metabolism pathways. Proteome-based stratification of primary melanomas defines three prognosis-related subtypes, namely, the ECM subtype, angiogenesis subtype (with a high metastasis rate), and cell proliferation subtype, which provides an essential framework for the utilization of specific targeted therapies for particular melanoma subtypes. The immune classification identifies three immune subtypes. Further analysis combined with an independent anti-PD-1 treatment cohort reveals that upregulation of the MAPK7-NFKB signaling pathway may facilitate T-cell recruitment and increase the sensitivity of patients to immunotherapy. In contrast, PRKDC may reduce the sensitivity of melanoma patients to immunotherapy by promoting DNA repair in melanoma cells. These results emphasize the clinical value of multi-omics data and have the potential to improve the understanding of melanoma treatment.

黑色素瘤是最常见的皮肤癌之一,转移率高,预后差。了解其分子发病机制对于改善其诊断和治疗至关重要。对207个治疗无效的黑色素瘤(原发性皮肤黑色素瘤(CM,n = 28)、原发性骶骨黑色素瘤(AM,n = 81)、原发性黏膜黑色素瘤(MM,n = 28)、转移性黑色素瘤(n = 27)和痣(n = 43))的多组学数据进行综合分析,有助于深入了解黑色素瘤的生物学特性。多变量分析显示,PRKDC扩增是黑色素瘤的预后分子。进一步的蛋白质组分析结合功能实验发现,PRKDC扩增的顺式效应可能会通过激活DNA修复和叶酸代谢途径导致肿瘤增殖。基于蛋白质组的原发性黑色素瘤分层定义了三种与预后相关的亚型,即ECM亚型、血管生成亚型(转移率高)和细胞增殖亚型,这为针对特定黑色素瘤亚型使用特定靶向疗法提供了重要框架。免疫分类确定了三种免疫亚型。结合独立的抗 PD-1 治疗队列进行的进一步分析表明,MAPK7-NFKB 信号通路的上调可能会促进 T 细胞的招募,并增加患者对免疫疗法的敏感性。与此相反,PRKDC 可通过促进黑色素瘤细胞的 DNA 修复,降低黑色素瘤患者对免疫疗法的敏感性。这些结果强调了多组学数据的临床价值,并有可能提高人们对黑色素瘤治疗的认识。
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引用次数: 0
Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide. 从结构上深入了解雷塔曲肽对 GLP-1R、GIPR 和 GCGR 的三重激动作用。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-17 DOI: 10.1038/s41421-024-00700-0
Wenzhuo Li, Qingtong Zhou, Zhaotong Cong, Qingning Yuan, Wenxin Li, Fenghui Zhao, H Eric Xu, Li-Hua Zhao, Dehua Yang, Ming-Wei Wang
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引用次数: 0
RhoA-mediated G12-G13 signaling maintains muscle stem cell quiescence and prevents stem cell loss. RhoA介导的G12-G13信号维持肌肉干细胞的静止状态并防止干细胞丢失。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-16 DOI: 10.1038/s41421-024-00696-7
Yundong Peng, Jingjing Du, Rui Li, Stefan Günther, Nina Wettschureck, Stefan Offermanns, Yan Wang, Andre Schneider, Thomas Braun

Multiple processes control quiescence of muscle stem cells (MuSCs), which is instrumental to guarantee long-term replenishment of the stem cell pool. Here, we describe that the G-proteins G12-G13 integrate signals from different G-protein-coupled receptors (GPCRs) to control MuSC quiescence via activation of RhoA. Comprehensive screening of GPCR ligands identified two MuSC-niche-derived factors, endothelin-3 (ET-3) and neurotensin (NT), which activate G12-G13 signaling in MuSCs. Stimulation with ET-3 or NT prevented MuSC activation, whereas pharmacological inhibition of ET-3 or NT attenuated MuSC quiescence. Inactivation of Gna12-Gna13 or Rhoa but not of Gnaq-Gna11 completely abrogated MuSC quiescence, which depleted the MuSC pool and was associated with accelerated sarcopenia during aging. Expression of constitutively active RhoA prevented exit from quiescence in Gna12-Gna13 mutant MuSCs, inhibiting cell cycle entry and differentiation via Rock and formins without affecting Rac1-dependent MuSC projections, a hallmark of quiescent MuSCs. The study uncovers a critical role of G12-G13 and RhoA signaling for active regulation of MuSC quiescence.

多种过程控制肌肉干细胞(MuSCs)的静止,这对保证干细胞池的长期补充至关重要。在这里,我们描述了G蛋白G12-G13整合来自不同G蛋白偶联受体(GPCR)的信号,通过激活RhoA控制MuSC的静止。对GPCR配体的全面筛选发现了两种来源于MuSC-niche的因子,即内皮素-3(ET-3)和神经营养素(NT),它们能激活MuSCs中的G12-G13信号。用ET-3或NT刺激可阻止MuSC的活化,而ET-3或NT的药理抑制可减轻MuSC的静止。Gna12-Gna13或Rhoa的失活,而不是Gnaq-Gna11的失活,可完全终止MuSC的静止,这将耗尽MuSC池,并与衰老过程中的肌少症加速有关。组成型活性 RhoA 的表达能阻止 Gna12-Gna13 突变体 MuSCs 从静止中退出,通过 Rock 和甲形蛋白抑制细胞周期的进入和分化,而不影响 Rac1 依赖性 MuSC 投射,这是静止 MuSCs 的标志。这项研究揭示了G12-G13和RhoA信号在主动调节MuSC静止过程中的关键作用。
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引用次数: 0
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。
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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。
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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。
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引用次数: 0
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Cell Discovery
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