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CNS 已集齐!近期使用 MCE 产品发表高分文章锦集 (一)

 

 

MCE (MedChemExpress) 是全球领先的科研化学品和生物活性化合物供应商。MCE 的产品范围覆盖各类抑制剂、激动剂、化合物库、天然产物、细胞因子及多种生化试剂盒。“确保客户拿到的每一个产品的质量” 是 MCE 的核心理念。现将 MCE 客户近期发表的部分高分文章作一分享,MCE 做您科研路上贴心的伙伴!
 

 

Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis.

Z-VAD(OMe)-FMK purchased from MCE.

细胞焦亡是机体重要的免疫机制,本质是由 gasdermin 介导的程序性坏死。焦亡执行蛋白 Gasdermin D (GSDMD) 是由炎症小体激活的 caspase-1 和 LPS 激活的 caspase-11/4/5 裂解。这种切割暴露 GSMDD-C-末端孔形成结构域。该研究表明,位点特异性 caspase-4/11 自动加工产生 P10 产物, 对裂解 GSDMD 和诱导细胞焦亡是充分和必要的。p10 形式自动加工 caspase-4/11 与 GSDMD-C 结构域以高亲和力结合。自动加工和未加工的 capase-11 的结构比较可鉴定一个被自动加工诱导的 β 折叠。在 caspase-4 / 11-GSDMD-C 复合物晶体结构中,β 折叠组织了一个 p10 形式 caspase-4/11 特异性的疏水性 GSDMD 结合界面。该结合促进了二聚化介导的 caspase 激活,使切割不依赖于裂解位点四肽序列。caspase-4/11-GSDMD-C 复合物晶体结构显示了相似的 GSDMD 识别模式。该研究揭示了一种前所未有的 caspases 底物靶向机制,疏水性界面为开发细胞焦亡 caspases 特异性抑制剂提供更多的可能。

The research shows site-specific caspase-4/11 autoprocessing, generating a p10 product, is required and sufficient for cleaving GSDMD and inducing pyroptosis. The p10-format processed caspase-4/11 binds the GSDMD-C domain with a high affinity. Structural comparison of autoprocessed and unprocessed capase-11 identifies a βsheet induced by the autoprocessing. In caspase-4/11-GSDMD-C complex crystal structures, the β sheet organizes a hydrophobic GSDMD-binding interface that is only possible for p10-form caspase-4/11. The binding promotes dimerization-mediated caspase activation, rendering a cleavage independently of the cleavage-site tetrapeptide sequence. Crystal structure of caspase-1-GSDMD-C complex shows a similar GSDMD-recognition mode.

Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex.

WIN55,212-2 Mesylate purchased from MCE.

选择性靶向 CB2 的药物有望治疗神经退行性疾病,炎症和疼痛,同时避免 CB1 介导的精神副作用,因此,CB2 激活和信号转导的机制对药物设计至关重要。该研究报道了人 CB2-Gi 信号复合物结合到激动剂 WIN 55,212-2 的冷冻电镜结构。3D 结构揭示了 WIN 55,212-2 的结合模式和将 CB2 激动剂与拮抗剂区分的结构决定簇。计算对接结果的进一步结构分析揭示了 CB2 和 CB1 之间在受体激活、配体识别和 Gi 偶联方面的差异。这些发现促进了大麻素系统的药物开发。

The study reports the cryo-EM structure of the human CB2-Gisignaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishingCB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and Gi coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system.

Integrating Mouse and Human Genetic Data to Move beyond GWAS and Identify Causal Genes in Cholesterol Metabolism.

Lovastatin purchased from MCE.

研究人员将小鼠肝脏共表达网络与人类脂质 GWAS 数据整合,以鉴定胆固醇和脂质代谢的调节因子。通过这种方法,鉴定出 48 个基因在小鼠中表现出复制,并与人类的血浆脂质特性相关,以及 X 染色体上的 6 个基因。基于功能性研究和人类脂质 GWAS 数据整合,他们发现 Sestrin1 是人类血浆胆固醇水平相关的致病基因,并且验证研究表明 Sestrin1 在多种小鼠模型中影响血浆胆固醇并调节胆固醇的生物合成。

The researchers develop a systematic approach that integrates mouse liver co-expression networks with human lipid GWAS data to identify regulators of cholesterol and lipid metabolism. Through their approach, they identified 48 genes showing replication in mice and associated with plasma lipid traits in humans and six genes on the X chromosome. Among these 54 genes, 25 have no previously identified role in lipid metabolism. Based on functional studies and integration with additional human lipid GWAS datasets, they pinpoint Sestrin1as a causal gene associated with plasma cholesterol levels in humans. The validation studies demonstrate that Sestrin1 influences plasma cholesterol in multiple mouse models and regulates cholesterol biosynthesis. The results highlight the power of combining mouse and human datasets for prioritization of human lipid GWAS loci and discovery of lipid genes.

A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol.

Bardoxolone, Tunicamycin, Gamitrinib TPP hexafluorophosphate purchased from MCE.

线粒体保真度与整个细胞体内平衡紧密相关,并且在衰老和各种病理学中受损。C/EBP 同源蛋白是综合应激反应的关键因素。研究人员将基因组工程和单倍体遗传学结合,鉴定出影响 C/EBP 同源蛋白 (CHOP) 诱导的基因。研究发现,线粒体蛋白酶 OMA1 和特征不明显的蛋白 DELE1 与 HRI 共同构成了由线粒体应激触发的缺失途径。机制上,压力诱导的 OMA1 激活致使 DELE1 被裂解成短片段在胞质中积累,并通过 C 末端结合并激活 HRI。这条通路的阻塞的利弊取决于线粒体紊乱的类型。除了核心途径,研究人员还通过比较基因筛选鉴定了一系列的其他调控因子。总而言之,这些发现可用于指导人类疾病背景下调节细胞对线粒体功能障碍应答的研究。

The researchers combine genome engineering and haploid genetics to unbiasedly identify genes that affect the induction of C/EBP homologous protein (CHOP), a key factor in the integrated stress response. The study shows that the mitochondrial protease OMA1 and the poorly characterized protein DELE1, together with HRI, constitute the missing pathway that is triggered by mitochondrial stress. Mechanistically, stress-induced activation of OMA1 causesDELE1to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. Obstruction of this pathway can be beneficial or adverse depending on the type of mitochondrial perturbation. In addition to the core pathway components, our comparative genetic screening strategy identifies a suite of additional regulators. 

Gut stem cell necroptosis by genome instability triggers bowel inflammation (Published online)

Necrostatin-1GSK-872, Z-VAD(OMe)-FMK purchased from MCE.

炎性肠病 (IBD) 是由遗传和环境之间的相互作用多种因素造成的。该研究报道,组蛋白甲基转移酶 SETDB1 的缺失参与了 IBD 的发病机理。研究发现,IBD 患者的 SETDB1 水平降低,而肠道干细胞中 SETDB1 降低的小鼠发展为自发性终末回肠炎和结肠炎。SETDB1 保护基因组稳定性,以及肠道干细胞中 SETDB1 的丢失释放了对内源性逆转录病毒的抑制。内源性逆转录病毒引起的过度病毒拟态触发了 ZBP1 依赖性坏死,不可逆转地破坏了上皮屏障的稳态并促进了肠道炎症。RIP3 的药物抑制作用在 SETDB1 缺陷型小鼠中具有治愈效果,这表明靶向肠道干细胞坏死有治疗严重 IBD 的潜力。

The research reports that deficiency in SETDB1, a histone methyltransferase that mediates the trimethylation of histone H3 atlysine 9, participates in the pathogenesis of IBD. They found that levels of SETDB1 are decreased in patients with IBD, and that mice with reduced SETDB1 in intestinal stem cells developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability, and the loss of SETDB1 in intestinal stem cells released repression of endogenous retroviruses (retrovirus-like elements with long repeats that, in humans, comprise approximately 8% of the genome). Excessive viral mimicry generated by motivated endogenous retroviruses triggered Z-DNA-binding protein 1 (ZBP1)-dependent necroptosis, which irreversibly disrupted homeostasis of the epithelial barrier and promoted bowel inflammation. Genome instability, reactive endogenous retroviruses, upregulation of ZBP1 and necroptosis were all seen in patients with IBD. Pharmaceutical inhibition of RIP3 showed a curative effect in SETDB1-deficient mice, which suggests that targeting necroptosis of intestinal stem cells may represent an approach for the treatment of severe IBD.

Structural basis of second-generation HIV integrase inhibitor action and viral resistance.

DolutegravirBictegravir purchased from MCE.

该研究揭示了 HIV 产生耐药性的结构机制和第二代 INSTI 的作用方式,为开发新型 INSTI 提供了方向。