CDK5RAP1

更新于：2025-05-07

基本信息

别名

C20orf34、C42、CDK5 activator-binding protein C42

+ [8]

简介

Methylthiotransferase that catalyzes the conversion of N6-(dimethylallyl)adenosine (i(6)A) to 2-methylthio-N6-(dimethylallyl)adenosine (ms(2)i(6)A) at position 37 (adjacent to the 3'-end of the anticodon) of four mitochondrial DNA-encoded tRNAs (Ser(UCN), Phe, Tyr and Trp) (PubMed:22422838, PubMed:25738458, PubMed:28981754). Essential for efficient and highly accurate protein translation by the ribosome (PubMed:22422838, PubMed:25738458, PubMed:28981754). Specifically inhibits CDK5 activation by CDK5R1 (PubMed:11882646). Essential for efficient mitochondrial protein synthesis and respiratory chain; shows pathological consequences in mitochondrial disease (PubMed:25738458).

关联

100 项与 CDK5RAP1 相关的临床结果

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100 项与 CDK5RAP1 相关的转化医学

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0 项与 CDK5RAP1 相关的专利（医药）

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116

项与 CDK5RAP1 相关的文献（医药）

2024-11-01·Advanced Biology

FAM136A as a Diagnostic Biomarker in Esophageal Cancer: Insights into Immune Infiltration, m6A Modification, Alternative Splicing, Cuproptosis, and the ceRNA Network

Article

作者: Wang, Zhulin ; Huang, Chunyao ; Fan, Wenbo ; Zhang, Guoqing ; Li, Xiangnan ; Li, Kaiyuan ; Wang, Zelong ; Sun, Shaowu ; Liu, Xu ; Zhao, Tianliang

AbstractFAM136A promotes the progression and metastasis of various tumors. However, there are few studies on the role of FAM136A in esophageal cancer (ESCA). The TCGA, GTEx, and GEO databases are employed to analyze the expression of FAM136A in ESCA, and qPCR and TMA experiments are performed for validation. Enrichment analyzes are performed to investigate the association of FAM136A expression with immune features, m6A modification, alternative splicing, cuproptosis, and the ceRNA network via bioinformatics analysis. FAM136A is highly expressed in ESCA and correlated with lymph node metastasis and overall survival (OS). Bioinformatics analysis suggested that FAM136A may participate in the following processes to promote ESCA development and progression: 1) Promotion of mast cells infiltration to influence the ESCA immune microenvironment, 2) HNRNPC upregulation to regulate m6A modification, 3) ALYREF upregulation to increase the occurrence of retained intron (RI) events, 4) CDK5RAP1 upregulation to achieve inhibition of tumor cell apoptosis, and 5) promotion of ESCA progression through the lncRNA SNHG15/hsa‐miR‐29c‐3p/FAM136A ceRNA network. FAM136A is a potential biomarker for ESCA diagnosis and treatment response evaluation, and the underlying mechanisms may be associated with immune infiltration, m6A modification, alternative splicing, cuproptosis, and the ceRNA regulatory network.

2023-10-02·Mycology

The disulphide cleavage derivative (C42-4) of 11′-deoxyverticillin A (C42) fails to induce apoptosis and genomic instability in HeLa cells

Article

作者: Hou, Bolin ; Jiang, Xuejun ; Li, Erwei ; Yang, Huaiyi

Our previous study revealed 11'-deoxyverticillin A (C42), a natural product isolated from the Ophiocordyceps-associated fungus Clonostachys rogersoniana and a member of the epipolythiodioxopiperazines (ETPs), induced both apoptosis and autophagy in HCT116 cells; however, the role of disulphide/polysulphide bridges of C42 in the regulation of autophagy remains unexplored. Here, we revealed that C42 activated both caspase-dependent apoptosis and autophagy in HeLa cells, whereas its disulphide cleavage derivative C42-4 failed to induce the cleavage of both caspase-3 and PARP-1. In contrast, both C42 and C42-4 increased the formation of autophagosomes, punctate staining of LC3, and the ratio of LC3-II to actin, suggesting that disulphide/polysulphide bridges are dispensable for the induction of the autophagic process. Moreover, we found that C42 but not C42-4 led to nuclear instability by increasing the formation of micronuclei and expression of phosphorylated histone H2AX (γ-H2AX), a widely used marker for DNA double strand breaks (DSBs), while Rad51, a protein pivotal for DNA repair, was decreased upon challenge with C42. These results demonstrate that the disulphide bonds in ETPs play an essential role in the induction of caspase-dependent apoptosis and nuclear stability.

2023-10-01·Journal of Pharmaceutical Analysis

Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission

Article

作者: Ouyang, Lan ; Gui, Zi-Kang ; He, Qing-Yu ; Wang, Yang ; Zhang, Jing ; Sun, Zheng-Hua ; Liang, Xiao-Ling ; Niu, Yu-Long ; Yu, Nan-Nan

Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of excessively asymmetric mitofission-associated cell death (MFAD) by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy. By screening a series of pan-inhibitors, we identified pracinostat, a pan-histone deacetylase (HDAC) inhibitor, as a novel MFAD inducer, that exhibited a significant anticancer effect on colorectal cancer (CRC) in vivo and in vitro. Pracinostat increased the expression of cyclin-dependent kinase 5 (CDK5) and induced its acetylation at residue lysine 33, accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynamin-related protein 1 (Drp1)-mediated mitochondrial peripheral fission. CRC cells with high level of CDK5 (CDK5-high) displayed midzone mitochondrial division that was associated with oncogenic phenotype, but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells. Mechanistically, pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor (MFF) to mitochondrial fission 1 protein (FIS1). Thus, our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells, which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.

项与 CDK5RAP1 相关的新闻（医药）

2024-09-22

·精准药物

【JMC】中科院上海药物研究所罗成等报道高活性LC3A/B共价抑制剂

细胞自噬（Autophagy）是维持细胞稳态的关键过程。通过降解细胞器、蛋白质、脂质、核酸和其他分子成分，细胞参与了一种微妙的循环策略，利用不同的构建模块来系统地解决营养缺乏问题。多项研究表明，自噬功能的失调与神经退行性疾病、代谢紊乱、癌症及炎症等多种疾病密切相关。因此，自噬通路中的关键蛋白，尤其是LC3家族蛋白，成为治疗这些疾病的重要靶标。然而，由于LC3的蛋白-蛋白相互作用界面缺乏明显的结合口袋，设计有效的LC3抑制剂成为药物开发中的一大难题。针对这一问题，中国科学院上海药物研究所罗成研究员团队通过基于结构的药物设计方法，开发了一种高效的LC3A/B共价抑制剂LC3in-C42。近日，该项研究发表于药物化学领域的著名期刊Journal of Medicinal Chemistry（J. Med. Chem. 2024, 67, 14, 12184–12204）【1】。该化合物通过优化共价弹头与非共价作用区，实现了对LC3蛋白的高效抑制，在蛋白水平和细胞水平上均展现了强大的自噬抑制能力。 LC3家族蛋白（LC3A、LC3B、LC3C）与其他自噬相关蛋白的相互作用对自噬体的形成至关重要，是自噬过程中不可或缺的核心蛋白，其负责自噬体的膜延伸和自噬底物的降解。但由于其相互作用界面平坦、缺乏可靶向的小分子结合口袋，现有的靶向LC3小分子抑制剂在活性和选择性方面存在显著不足，限制了其在疾病治疗中的应用。为应对这一挑战，罗成研究员团队利用共价抑制剂设计策略，成功设计了新型化合物LC3in-C42。该化合物基于之前开发的LC3抑制剂DC-LC3in-D5，通过对化合物的共价弹头和非共价结合部分进行优化，使其能够更好地靶向LC3蛋白并抑制自噬。在这一研究中，研究团队详细探讨了LC3in-C42的结构-活性关系（SARs），并成功地通过分子杂交的方式将吲哚和双氯代苯片段结合，设计出了拥有极高活性的LC3抑制剂。 LC3共价抑制剂的设计共价抑制剂近年来因其靶向性强、作用持久，在药物开发中备受关注。通过分析LC3复合物的晶体结构，研究团队对DC-LC3in类化合物进行了深入研究，并将其分解为共价弹头与非共价作用区两部分。在探索构效关系时，研究发现三级胺的引入提升了共价弹头的活性，吲哚和双氯代苯的非共价结合部分也显著增强了结合力。基于分子杂交策略，研究人员将LC3in-C32与LC3in-C41的关键片段进行整合，最终合成了LC3in-C42。分子模拟结果显示：化合物LC3in-C42通过与LC3的疏水口袋HP2的增强结合，实现了共价与非共价作用的平衡，显著提升了活性。图1. LC3in-C42分子优化设计方案及分子对接预测LC3in-C42与LC3B的结合模式体外实验验证通过AlphaScreen实验，研究团队测试了LC3in-C42在体外的抑制效果。结果表明，LC3in-C42的IC50值仅为7.6 nM，远远优于此前的DC-LC3in-D5抑制剂（IC50值为51.68 nM）与LC3in-C32抑制剂IC50值为33.61 nM）。这标志着该化合物在活性方面实现了质的飞跃。图2. AlphaScreen实验表明LC3in-C42体外活性显著提升在细胞实验中，LC3in-C42同样表现出卓越的自噬抑制能力。研究人员通过免疫荧光实验和自噬流实验，验证了该化合物在低浓度下即能有效抑制自噬体的形成，并阻止LC3-II的脂化过程。相比于DC-LC3in-D5，LC3in-C42在5 μM的浓度下即可显著抑制自噬过程，而DC-LC3in-D5需要更高的浓度（20 μM）才能达到相同的效果。自噬流分析表明，LC3in-C42能够有效阻止P62的降解，进一步证明了其在细胞自噬过程中的显著抑制作用。此外，该化合物在细胞内的热稳定性测试（CETSA）结果显示，LC3in-C42能够选择性地靶向LC3A/B蛋白，而对GABARAP等其他LC3家族蛋白的影响较小。这一发现表明，LC3in-C42不仅在活性上远超DC-LC3in-D5，在选择性方面也表现出更优异的特性。图3. 体外实验验证表明LC3in-C42的自噬抑制能力显著强于DC-LC3in-D5 应用展望 LC3in-C42作为一种新型的共价抑制剂，不仅为深入研究LC3蛋白在自噬过程中的作用提供了重要工具，也为治疗与自噬相关的疾病，如神经退行性疾病、癌症等，提供了潜在的药物开发路径。未来的研究将进一步优化LC3in-C42的药物性和体内稳定性，以确保其在临床应用中的安全性和有效性。该研究通过结构药物设计开发了新型LC3A/B抑制剂LC3in-C42。通过优化共价弹头和非共价作用区，LC3in-C42展现出优异的活性和选择性，并在体外和细胞水平上有效抑制自噬过程。该化合物有望成为研究自噬机制的重要工具，并为未来自噬相关疾病的治疗提供了新的药物候选。参考文献 [1] Zhou Z, Huang S, Fan S, Li X, Wang C, Yu W, Du D, Zhang Y, et al. Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor[J]. Journal of Medicinal Chemistry, 2024, 67(14): 12184-12204. 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

2024-09-05

·精准药物

【JMC】靶向LC3A/B的共价抑制剂

英文原题：Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor 通讯作者：付伟（复旦大学），陈凯先、罗成（中国科学院上海药物研究所）作者：Zhenfei Zhou, Siqi Huang, Shijie Fan, Xueyuan Li, Chengyu Wang, Wanlin Yu, Daohai Du, Yuanyuan Zhang, Kaixian Chen*, Wei Fu*, and Cheng Luo* 细胞自噬（Autophagy）是一种在真核生物中高度保守的细胞稳态维持机制，具体为通过溶酶体（Lysosome）将细胞内组分进行降解和回收的过程。多项研究表明，细胞自噬紊乱与多种疾病相关，其中包括神经退行性疾病、感染、炎症、代谢异常、癌症和衰老等。因此，细胞自噬通路相关蛋白是疾病治疗的潜在干预靶标。LC3家族蛋白参与了自噬体的扩展延伸和封闭的过程，是自噬体形成和自噬底物降解至关重要的核心蛋白。 LC3蛋白执行功能主要通过其蛋白相互作用界面，但是其蛋白-蛋白质相互作用界面缺少结合位点，难以利用小分子化合物进行靶向。因此已报道的小分子化合物普遍活性低、选择性差，细胞活性弱。在前期工作中，中国科学院上海药物研究所罗成研究员利用共价抑制剂设计策略结合多种分子生物学手段，开发得到了首个具有明确活性的LC3共价化合物DC-LC3in-D5（Angew. Chem. Int. Ed., 2021, 60, 26105），其体外破坏蛋白相互作用活性达到200 nM，并在细胞层面能够实现自噬抑制。近日，罗成研究员团队在已有成果的基础上再次取得重要进展。通过分析团队获得的复合物晶体结构，将DC-LC3in类化合物分为共价弹头与非共价作用区两个部分重点探索构效关系，针对共价弹头部分的改造结果说明相隔两个亚甲基的三级胺对于活性有所提升，非共价部分的改造结果说明吲哚片段与双氯代苯片段对活性提升的作用十分明显。通过将优势片段吲哚与双氯代苯进行分子杂交的设计手段，得到了化合物LC3in-C42，使得小分子化合物加强了与LC3的疏水口袋HP2的非共价结合，实现了共价/非共价亲和力的平衡（图1）。图1. 分子对接预测LC3in-C42与LC3B的结合模式，并与现有的分子进行叠合比较。 LC3in-C42体外通过AlphaScreen实验，表明其IC50值为7.6 nM。相较于DC-LC3in-D5显著提升（图2）。在细胞层面上，LC3in-C42展现出比DC-LC3inD5更强的自噬抑制能力，自噬流实验与免疫荧光实验表明，相较于DC-LC3in-D5，LC3in-C42可以在更低的浓度下抑制自噬（图3）。图2. 结构优化使得体外活性显著提升图3. 自噬流实验与免疫荧光表明LC3in-C42的自噬抑制能力显著强于DC-LC3in-D5 在本研究中，该团队利用基于结构的药物设计策略和分子杂交手段，开发了截至目前为止活性最强的靶向LC3A/B的小分子共价抑制剂LC3in-C42。该化合物可作为一个优秀的化学探针用于探究LC3相关的自噬功能与机制研究，同时也为自噬相关疾病提供了一个潜在的先导化合物。相关研究成果发表在药物化学领域经典期刊Journal of Medicinal Chemistry 上。复旦大学与中科院上海药物研究所/中科中山药物创新研究院联合培养博士生周振飞、上海药物研究所博士生黄思琦、中科中山药创院助理研究员范仕杰为该论文共同第一作者，复旦大学付伟教授、上海药物研究所陈凯先院士、罗成研究员为该论文的共同通讯作者。 Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor Zhenfei Zhou, Siqi Huang, Shijie Fan, Xueyuan Li, Chengyu Wang, Wanlin Yu, Daohai Du, Yuanyuan Zhang, Kaixian Chen*, Wei Fu*, and Cheng Luo* J. Med. Chem. 2024, 67, 14, 12184–12204 Publication Date: July 15, 2024 https://doi.org/10.1021/acs.jmedchem.4c00898 © 2024 American Chemical Society 药物筛选中心（暨南大学）对外提供新药筛选服务声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓