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Reflections from Nobel laureates in chemistry 诺贝尔化学奖获得者的思考
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.016

Since the first award in 1901, the Nobel Prize has come to signify the pinnacle of scientific achievement. In this Voices piece in the August special issue of Cell Chemical Biology entitled “Bridging chemistry and biology,” we ask Nobel laureates to reflect on the impact the prize had on them. We learn how it affected their life or work, their outlook on science, the lessons learned, and their advice for the next generation of scientists.

自 1901 年首次颁奖以来,诺贝尔奖已成为科学成就巅峰的象征。在《细胞化学生物学》八月特刊题为 "化学与生物学的桥梁 "的这篇评论文章中,我们请诺贝尔奖获得者回顾诺贝尔奖对他们的影响。我们将了解诺贝尔奖对他们的生活和工作产生了怎样的影响、他们的科学观、经验教训以及他们对下一代科学家的建议。
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引用次数: 0
Septins promote macrophage pyroptosis by regulating gasdermin D cleavage and ninjurin-1-mediated plasma membrane rupture 赛普特蛋白通过调控气敏D的裂解和ninjurin-1介导的质膜破裂促进巨噬细胞的脓毒症
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.003

The septin cytoskeleton is primarily known for roles in cell division and host defense against bacterial infection. Despite recent insights, the full breadth of roles for septins in host defense is poorly understood. In macrophages, Shigella induces pyroptosis, a pro-inflammatory form of cell death dependent upon gasdermin D (GSDMD) pores at the plasma membrane and cell surface protein ninjurin-1 (NINJ1) for membrane rupture. Here, we discover that septins promote macrophage pyroptosis induced by lipopolysaccharide (LPS)/nigericin and Shigella infection, but do not affect cytokine expression or release. We observe that septin filaments assemble at the plasma membrane, and cleavage of GSDMD is impaired in septin-depleted cells. We found that septins regulate mitochondrial dynamics and the expression of NINJ1. Using a Shigella-zebrafish infection model, we show that septin-mediated pyroptosis is an in vivo mechanism of infection control. The discovery of septins as a mediator of pyroptosis may inspire innovative anti-bacterial and anti-inflammatory treatments.

人们主要了解隔膜细胞骨架在细胞分裂和宿主防御细菌感染中的作用。尽管最近有了新的认识,但人们对隔膜在宿主防御中的全部作用还知之甚少。在巨噬细胞中,志贺氏杆菌会诱导热噬,这是一种促炎性细胞死亡形式,依赖于质膜上的 gasdermin D(GSDMD)孔和细胞表面蛋白 ninjurin-1(NINJ1)使膜破裂。在这里,我们发现隔蛋白能促进巨噬细胞在脂多糖(LPS)/尼革菌素和志贺氏杆菌感染诱导下的热休克,但不影响细胞因子的表达或释放。我们观察到,隔蛋白丝在细胞质膜上聚集,而GSDMD的裂解在隔蛋白缺失的细胞中受损。我们发现,隔膜调节线粒体动力学和 NINJ1 的表达。通过志贺氏菌-斑马鱼感染模型,我们发现隔蛋白介导的热蛋白沉积是一种体内感染控制机制。发现隔蛋白是热蛋白沉积的介质可能会激发创新的抗菌和抗炎治疗方法。
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引用次数: 0
AspSnFR: A genetically encoded biosensor for real-time monitoring of aspartate in live cells AspSnFR:用于实时监测活细胞中天冬氨酸的基因编码生物传感器
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.05.002

Aspartate is crucial for nucleotide synthesis, ammonia detoxification, and maintaining redox balance via the malate-aspartate-shuttle (MAS). To disentangle these multiple roles of aspartate metabolism, tools are required that measure aspartate concentrations in real time and in live cells. We introduce AspSnFR, a genetically encoded green fluorescent biosensor for intracellular aspartate, engineered through displaying and screening biosensor libraries on mammalian cells. In live cells, AspSnFR is able to precisely and quantitatively measure cytosolic aspartate concentrations and dissect its production from glutamine. Combining high-content imaging of AspSnFR with pharmacological perturbations exposes differences in metabolic vulnerabilities of aspartate levels based on nutrient availability. Further, AspSnFR facilitates tracking of aspartate export from mitochondria through SLC25A12, the MAS’ key transporter. We show that SLC25A12 is a rapidly responding and direct route to couple Ca2+ signaling with mitochondrial aspartate export. This establishes SLC25A12 as a crucial link between cellular signaling, mitochondrial respiration, and metabolism.

天冬氨酸对核苷酸合成、氨解毒以及通过苹果酸-天冬氨酸转换器(MAS)维持氧化还原平衡至关重要。要厘清天冬氨酸代谢的这些多重作用,需要能在活细胞中实时测量天冬氨酸浓度的工具。我们介绍的 AspSnFR 是一种经基因编码的细胞内天冬氨酸绿色荧光生物传感器,它是通过在哺乳动物细胞上显示和筛选生物传感器文库而设计出来的。在活细胞中,AspSnFR 能够精确地定量测量细胞膜天冬氨酸的浓度,并从谷氨酰胺中分解出天冬氨酸。将 AspSnFR 的高含量成像与药理学扰动相结合,可揭示天冬氨酸水平在营养物质可用性基础上的代谢脆弱性差异。此外,AspSnFR 还有助于跟踪天门冬氨酸通过 MAS 的关键转运体 SLC25A12 从线粒体输出的情况。我们的研究表明,SLC25A12 是将 Ca2+ 信号与线粒体天冬氨酸输出结合起来的快速反应和直接途径。这证明 SLC25A12 是细胞信号、线粒体呼吸和新陈代谢之间的关键纽带。
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引用次数: 0
Regulated induced proximity targeting chimeras—RIPTACs—A heterobifunctional small molecule strategy for cancer selective therapies 调控诱导接近靶向嵌合体--RIPTACs--用于癌症选择性疗法的异功能小分子策略
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.005

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.

我们描述了一种称为 "调控诱导接近性靶向嵌合体 "或 "RIPTACs "的蛋白质接近性诱导治疗模式:异功能小分子能在肿瘤细胞中选择性表达的靶蛋白(TP)与细胞存活所必需的泛表达蛋白之间产生稳定的三元复合物。由此产生的蛋白-蛋白相互作用(PPI)会削弱必需蛋白的功能,从而导致表达 TP 的细胞选择性死亡。这种方法利用细胞内不同表达的蛋白质作为新型癌症靶点,其优点是不要求靶点是疾病的驱动因素。在这项化学生物学研究中,我们设计的 RIPTACs 含有针对模型 TP 的配体,该配体通过连接体与 JQ1(BRD4)或 BI2536(PLK1)等效应配体或 TMX3013 或 dinaciclib 等 CDK 抑制剂相连。RIPTACs 可选择性地在表达 HaloTag-FKBP 靶点的细胞中聚集,形成协同作用的细胞内三元复合物,并诱导靶点表达细胞产生抗增殖反应。
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引用次数: 0
The chemistry of electrical signaling in sodium channels from bacteria and beyond 细菌等钠离子通道中的电信号化学反应
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.010

Electrical signaling is essential for all fast processes in biology, but its molecular mechanisms have been uncertain. This review article focuses on studies of bacterial sodium channels in order to home in on the essential molecular and chemical mechanisms underlying transmembrane ion conductance and voltage-dependent gating without the overlay of complex protein interactions and regulatory mechanisms in mammalian sodium channels. This minimalist approach has yielded a nearly complete picture of sodium channel function at the atomic level that are mostly conserved in mammalian sodium channels, including sodium selectivity and conductance, voltage sensing and activation, electromechanical coupling to pore opening and closing, slow inactivation, and pathogenic dysfunction in a debilitating channelopathy. Future studies of nature’s simplest sodium channels may continue to yield key insights into the fundamental molecular and chemical principles of their function and further elucidate the chemical basis of electrical signaling.

电信号对生物学中的所有快速过程都至关重要,但其分子机制却一直不确定。这篇综述文章侧重于对细菌钠通道的研究,以便深入探讨跨膜离子传导和电压依赖性门控的基本分子和化学机制,而不涉及哺乳动物钠通道中复杂的蛋白质相互作用和调控机制。这种简约方法在原子水平上几乎完整地描述了哺乳动物钠通道的功能,其中包括钠的选择性和传导性、电压感应和激活、与孔打开和关闭的机电耦合、缓慢失活以及使人衰弱的通道病变中的致病功能障碍。未来对自然界最简单的钠通道的研究可能会继续深入了解其功能的基本分子和化学原理,并进一步阐明电信号的化学基础。
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引用次数: 0
Meet the authors: Xueqin Jin, Jian Huang, Huan Wang, Kan Wang, and Nieng Yan 与作者见面金雪琴、黄健、王欢、王侃和严能
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.009

In an interview with Dr. Samantha Nelson, a scientific editor of Cell Chemical Biology, the authors of the perspective entitled “A versatile residue numbering scheme for Nav and Cav channels” share their thoughts on life as scientists.

在接受《细胞化学生物学》(Cell Chemical Biology)科学编辑萨曼莎-尼尔森博士(Samantha Nelson)的采访时,题为《Nav 和 Cav 通道的通用残基编号方案》的作者分享了他们对科学家生活的看法。
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引用次数: 0
Synthetic gene circuit evolution: Insights and opportunities at the mid-scale 合成基因回路进化:中等规模的洞察力和机遇
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.05.018

Directed evolution focuses on optimizing single genetic components for predefined engineering goals by artificial mutagenesis and selection. In contrast, experimental evolution studies the adaptation of entire genomes in serially propagated cell populations, to provide an experimental basis for evolutionary theory. There is a relatively unexplored gap at the middle ground between these two techniques, to evolve in vivo entire synthetic gene circuits with nontrivial dynamic function instead of single parts or whole genomes. We discuss the requirements for such mid-scale evolution, with hypothetical examples for evolving synthetic gene circuits by appropriate selection and targeted shuffling of a seed set of genetic components in vivo. Implementing similar methods should aid the rapid generation, functionalization, and optimization of synthetic gene circuits in various organisms and environments, accelerating both the development of biomedical and technological applications and the understanding of principles guiding regulatory network evolution.

定向进化侧重于通过人工诱变和选择优化单个基因元件,以实现预定的工程目标。相比之下,实验进化研究的是整个基因组在连续繁殖的细胞群中的适应性,为进化理论提供实验基础。在这两种技术的中间地带有一个相对尚未开发的空白,即在体内进化具有非难动态功能的整个合成基因回路,而不是单个部分或整个基因组。我们讨论了这种中等规模进化的要求,并举例说明了通过适当选择和有针对性地在体内对基因元件种子集进行洗牌来进化合成基因回路的假设。类似方法的实施将有助于在各种生物体和环境中快速生成、功能化和优化合成基因回路,从而加快生物医学和技术应用的发展,并加深对调控网络进化原理的理解。
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引用次数: 0
Therapeutic potential of cis-targeting bispecific antibodies 顺式靶向双特异性抗体的治疗潜力
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.004

The growing clinical success of bispecific antibodies (bsAbs) has led to rapid interest in leveraging dual targeting in order to generate novel modes of therapeutic action beyond mono-targeting approaches. While bsAbs that bind targets on two different cells (trans-targeting) are showing promise in the clinic, the co-targeting of two proteins on the same cell surface through cis-targeting bsAbs (cis-bsAbs) is an emerging strategy to elicit new functionalities. This includes the ability to induce proximity, enhance binding to a target, increase target/cell selectivity, and/or co-modulate function on the cell surface with the goal of altering, reversing, or eradicating abnormal cellular activity that contributes to disease. In this review, we focus on the impact of cis-bsAbs in the clinic, their emerging applications, and untangle the intricacies of improving bsAb discovery and development.

双特异性抗体(bsAbs)在临床上取得了越来越大的成功,这使人们对利用双靶向技术产生超越单靶向方法的新型治疗作用模式产生了浓厚的兴趣。结合两个不同细胞靶点的 bsAbs(反式靶向)在临床上显示出前景,而通过顺式靶向 bsAbs(顺式 bsAbs)共同靶向同一细胞表面的两种蛋白质则是激发新功能的新兴策略。这包括诱导接近、增强与靶点的结合、提高靶点/细胞选择性和/或共同调节细胞表面功能的能力,目的是改变、逆转或消除导致疾病的异常细胞活动。在这篇综述中,我们将重点讨论顺式 bsAb 在临床中的影响、它们的新兴应用,并揭示改进 bsAb 发现和开发的复杂性。
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引用次数: 0
Carolyn Bertozzi: Building new bonds between molecules, fields, and communities 卡罗琳-贝托兹:在分子、领域和社区之间建立新的联系
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.015
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引用次数: 0
Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway. 人类 AKR1C3 与 GPR84 的激动剂结合,并参与扩展的多胺途径。
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-09 DOI: 10.1016/j.chembiol.2024.07.011
Natavan Dudkina, Hyun Bong Park, Deguang Song, Abhishek Jain, Sajid A Khan, Richard A Flavell, Caroline H Johnson, Noah W Palm, Jason M Crawford

Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product "sperminal" is reduced to "sperminol." Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.

人类醛酮还原酶家族 1 成员 C3(AKR1C3)表达的改变与多种癌症的不良预后、铁中毒抵抗和代谢性疾病有关。尽管AKR1C3具有重要的临床意义,但其内源生化作用仍未完全明确。利用非靶向代谢组学,我们发现了 AKR1C3 介导的一种主要转化,其中精胺氧化产物 "精胺 "被还原为 "精胺醇"。精胺会导致DNA损伤并激活DNA双链断裂反应,而精胺醇则会在体外诱导自噬。AKR1C3 还能拉低酰基吡喃酮,而吡喃酮-211 能抑制 AKR1C3 的活性。通过 G 蛋白偶联受体配体筛选,我们确定 pyrone-211 也是半orphan 受体 GPR84 的强效激动剂。令人吃惊的是,哺乳动物脂肪酸合成酶在体外产生酰基吡咯酮,而这种产生受 NADPH 的调节。综上所述,我们的研究支持 AKR1C3 在扩展的多胺通路中的调控作用,以及将脂肪酸合成和 NADPH 水平与 GPR84 信号联系起来的模型。
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引用次数: 0
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Cell Chemical Biology
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