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Heterogeneity of tethered agonist signaling in adhesion G protein-coupled receptors 粘附 G 蛋白偶联受体中系留激动剂信号的异质性
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.03.004

Adhesion G protein-coupled receptor (aGPCR) signaling influences development and homeostasis in a wide range of tissues. In the current model for aGPCR signaling, ligand binding liberates a conserved sequence that acts as an intramolecular, tethered agonist (TA), yet this model has not been evaluated systematically for all aGPCRs. Here, we assessed the TA-dependent activities of all 33 aGPCRs in a suite of transcriptional reporter, G protein activation, and β-arrestin recruitment assays using a new fusion protein platform. Strikingly, only ∼50% of aGPCRs exhibited robust TA-dependent activation, and unlike other GPCR families, aGPCRs showed a notable preference for G12/13 signaling. AlphaFold2 predictions assessing TA engagement in the predicted intramolecular binding pocket aligned with the TA dependence of the cellular responses. This dataset provides a comprehensive resource to inform the investigation of all human aGPCRs and for targeting aGPCRs therapeutically.

粘附 G 蛋白偶联受体(aGPCR)信号传导影响着多种组织的发育和稳态。在目前的 aGPCR 信号传导模型中,配体结合会释放出一个保守序列,该序列可充当分子内的系链激动剂(TA),但这一模型尚未针对所有 aGPCR 进行过系统评估。在这里,我们利用一个新的融合蛋白平台,在一系列转录报告、G 蛋白激活和 β - 逮捕素招募试验中评估了所有 33 个 aGPCR 的 TA 依赖性活性。令人吃惊的是,只有 50% 的 aGPCR 表现出强大的 TA 依赖性激活,而且与其他 GPCR 家族不同,aGPCR 对 G12/13 信号转导表现出明显的偏好。AlphaFold2 预测评估了 TA 在预测的分子内结合口袋中的参与情况,这与细胞反应的 TA 依赖性相一致。该数据集提供了一个全面的资源,为研究所有人类 aGPCRs 和治疗 aGPCRs 提供了信息。
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引用次数: 0
Feel the breeze: Opening the therapeutic window with RIPTACs and induced proximity 感受微风利用 RIPTAC 和诱导接近打开治疗之窗
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.013
Kyle Mangano , Patrick Ryan Potts

In this issue of Cell Chemical Biology, Raina et al.1 demonstrate proof of concept of a new chemical induced proximity strategy for targeted cancer therapeutics. Building on a recent surge in induced proximity modalities, RIPTACs represent a novel approach that offers promise in treating cancers with improved safety profiles.

在本期《细胞化学生物学》(Cell Chemical Biology)杂志上,Raina 等人1 展示了一种新型化学诱导接近策略的概念验证,该策略可用于癌症靶向治疗。RIPTACs 是一种新型的诱导接近模式,它以最近激增的诱导接近模式为基础,有望在治疗癌症的同时提高安全性。
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引用次数: 0
Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria 鉴定治疗疟疾的强效可逆哌啶羧酰胺类物种选择性口服活性蛋白酶体抑制剂
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.001
Aloysus Lawong , Suraksha Gahalawat , Sneha Ray , Nhi Ho , Yan Han , Kurt E. Ward , Xiaoyi Deng , Zhe Chen , Ashwani Kumar , Chao Xing , Varun Hosangadi , Kate J. Fairhurst , Kyuto Tashiro , Glen Liszczak , David M. Shackleford , Kasiram Katneni , Gong Chen , Jessica Saunders , Elly Crighton , Arturo Casas , Margaret A. Phillips

Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome β5 active-site (Pfβ5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto β7. Inhibition of Pfβ5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the β5/β6/β3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.

由于抗药性威胁着治疗计划,疟疾仍然是一个全球关注的健康问题。我们通过表型筛选确定了一种具有抗疟疾活性的哌啶甲酰胺(SW042)。对 SW042 产生抗药性的恶性疟原虫(Pf)寄生虫进行筛选后发现,Pf_蛋白酶体 β5 活性位点(Pfβ5)发生了点突变。一种强效类似物(SW584)在人类疟疾小鼠模型中显示出口服后的疗效。SW584 产生抗药性的倾向性较低(抗药性最小接种量 [MIR] >109),并且与双氢青蒿素具有协同作用。通过在 β7 上引入 His8 标记,促进了 Pf 蛋白酶体的纯化。抑制 Pfβ5 与杀死寄生虫有关,但不抑制人类蛋白酶体同工酶,也不显示细胞毒性。Pf_proteasome_SW584的低温电子显微镜(cryo-EM)结构显示,SW584与催化苏氨酸远端非共价结合,位于β5/β6/β3亚基界面上一个未探索的口袋中,该口袋在Pf和人类蛋白酶体之间存在物种差异。鉴定出一种可逆的、具有物种选择性的、口服活性的、低阻力倾向的系列药物,为这一重要靶点的药物治疗提供了一条途径。
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引用次数: 0
Precision epigenetic editing: Technological advances, enduring challenges, and therapeutic applications 精准表观遗传编辑:技术进步、持久挑战和治疗应用
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.007
Goldie V. Roth , Isabella R. Gengaro , Lei S. Qi

The epigenome is a complex framework through which gene expression is precisely and flexibly modulated to incorporate heritable memory and responses to environmental stimuli. It governs diverse cellular processes, including cell fate, disease, and aging. The need to understand this system and precisely control gene expression outputs for therapeutic purposes has precipitated the development of a diverse set of epigenetic editing tools. Here, we review the existing toolbox for targeted epigenetic editing, technical considerations of the current technologies, and opportunities for future development. We describe applications of therapeutic epigenetic editing and their potential for treating disease, with a discussion of ongoing delivery challenges that impede certain clinical interventions, particularly in the brain. With simultaneous advancements in available engineering tools and appropriate delivery technologies, we predict that epigenetic editing will increasingly cement itself as a powerful approach for safely treating a wide range of disorders in all tissues of the body.

表观基因组是一个复杂的框架,通过它可以精确、灵活地调节基因表达,将遗传记忆和对环境刺激的反应结合起来。它支配着多种细胞过程,包括细胞命运、疾病和衰老。出于治疗目的,人们需要了解这一系统并精确控制基因表达输出,这促进了一系列表观遗传编辑工具的开发。在此,我们回顾了现有的定向表观遗传编辑工具箱、当前技术的技术考虑因素以及未来发展的机遇。我们介绍了治疗性表观遗传编辑的应用及其治疗疾病的潜力,并讨论了目前阻碍某些临床干预措施(尤其是脑部干预措施)的交付难题。我们预测,随着现有工程工具和适当传输技术的同步发展,表观遗传编辑将日益成为安全治疗身体各组织各种疾病的有力方法。
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引用次数: 0
A versatile residue numbering scheme for Nav and Cav channels Nav 和 Cav 信道的通用残差编号方案
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.008
Xueqin Jin , Jian Huang , Huan Wang , Kan Wang , Nieng Yan

Voltage-gated sodium (Nav) and calcium (Cav) channels are responsible for the initiation of electrical signals. They have long been targeted for the treatment of various diseases. The mounting number of cryoelectron microscopy (cryo-EM) structures for diverse subtypes of Nav and Cav channels from multiple organisms necessitates a generic residue numbering system to establish the structure-function relationship and to aid rational drug design or optimization. Here we suggest a structure-based residue numbering scheme, centering around the most conserved residues on each of the functional segments. We elaborate the generic numbers through illustrative examples, focusing on representative drug-binding sites of eukaryotic Nav and Cav channels. We also extend the numbering scheme to compare common disease mutations among different Nav subtypes. Application of the generic residue numbering scheme affords immediate insights into hotspots for pathogenic mutations and critical loci for drug binding and will facilitate drug discovery targeting Nav and Cav channels.

电压门控钠(Nav)和钙(Cav)通道负责启动电信号。长期以来,它们一直是治疗各种疾病的靶标。来自多种生物体的不同亚型 Nav 和 Cav 通道的冷冻电子显微镜(cryo-EM)结构越来越多,这就需要一个通用的残基编号系统来建立结构-功能关系,并帮助合理的药物设计或优化。在此,我们围绕每个功能片段上最保守的残基,提出了基于结构的残基编号方案。我们以真核生物 Nav 和 Cav 通道的代表性药物结合位点为例,详细阐述了通用编号。我们还扩展了编号方案,以比较不同 Nav 亚型之间的常见疾病突变。应用通用残基编号方案可立即了解致病突变的热点和药物结合的关键位点,并将促进针对 Nav 和 Cav 通道的药物发现。
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引用次数: 0
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
Thomas R. Cech, Emmanuelle Charpentier, Aaron Ciechanover, Robert J. Lefkowitz, Kurt Wüthrich

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
The art of designed coiled-coils for the regulation of mammalian cells 设计用于调节哺乳动物细胞的盘绕线圈的艺术。
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.06.001

Synthetic biology aims to engineer complex biological systems using modular elements, with coiled-coil (CC) dimer-forming modules are emerging as highly useful building blocks in the regulation of protein assemblies and biological processes. Those small modules facilitate highly specific and orthogonal protein-protein interactions, offering versatility for the regulation of diverse biological functions. Additionally, their design rules enable precise control and tunability over these interactions, which are crucial for specific applications. Recent advancements showcase their potential for use in innovative therapeutic interventions and biomedical applications. In this review, we discuss the potential of CCs, exploring their diverse applications in mammalian cells, such as synthetic biological circuit design, transcriptional and allosteric regulation, cellular assemblies, chimeric antigen receptor (CAR) T cell regulation, and genome editing and their role in advancing the understanding and regulation of cellular processes.

合成生物学旨在利用模块化元素设计复杂的生物系统,而形成盘绕线圈(CC)二聚体的模块正在成为调控蛋白质组装和生物过程的非常有用的构件。这些小模块可促进蛋白质与蛋白质之间高度特异和正交的相互作用,为调控各种生物功能提供了多功能性。此外,它们的设计规则能够实现对这些相互作用的精确控制和可调谐性,这对特定应用至关重要。最近的进展展示了它们在创新治疗干预和生物医学应用方面的潜力。在这篇综述中,我们将讨论 CCs 的潜力,探讨它们在哺乳动物细胞中的各种应用,如合成生物电路设计、转录和异生调控、细胞组装、嵌合抗原受体 (CAR) T 细胞调控和基因组编辑,以及它们在促进对细胞过程的理解和调控方面的作用。
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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
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
Dominik Brokatzky , Margarida C. Gomes , Stevens Robertin , Carolina Albino , Sydney L. Miles , Serge Mostowy

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
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
Kanak Raina , Chris D. Forbes , Rebecca Stronk , Jonathan P. Rappi Jr. , Kyle J. Eastman , Nilesh Zaware , Xinheng Yu , Hao Li , Amit Bhardwaj , Samuel W. Gerritz , Mia Forgione , Abigail Hundt , Madeline P. King , Zoe M. Posner , Allison D. Correia , Andrew McGovern , David E. Puleo , Rebekka Chenard , James J. Mousseau , J. Ignacio Vergara , Craig M. Crews

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
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Cell Chemical Biology
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