更新于：2024-11-01

ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1

更新于：2024-11-01

基本信息

别名

clpC1

简介-

关联

项与 ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1 相关的药物

UdSBI-4377

靶点

ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1

作用机制

ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1抑制剂

在研机构

Boehringer Ingelheim Ltd.

原研机构

Boehringer Ingelheim Ltd.

在研适应症

分枝杆菌感染

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

Clp-targeting BacPROTAC

靶点

ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1 x ATP 依赖性蛋白酶 ATP 结合亚基 ClpC2

作用机制

ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1抑制剂 [+1]

在研机构

上海勃林格殷格翰药业有限公司 [+1]

原研机构

Vienna Biocenter [+1]

在研适应症

结核

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

UdSBI-0545

靶点

ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1

作用机制

ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1抑制剂

在研机构

Boehringer Ingelheim Ltd.

原研机构

Boehringer Ingelheim Ltd.

在研适应症

分枝杆菌感染

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1 相关的临床结果

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100 项与 ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1 相关的转化医学

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0 项与 ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1 相关的专利（医药）

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项与 ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1 相关的文献（医药）

2024-07-01·Plant, Cell & Environment

Mutant noxy8 exposes functional specificities between the chloroplast chaperones CLPC1 and CLPC2 in the response to organelle stress and plant defence

Article

作者: Izquierdo, Yovanny ; López, Bran ; Pulido, Pablo ; Castresana, Carmen ; Cascón, Tomás ; Zamarreño, Ángel M. ; García‐Mina, José M.

AbstractChloroplast function is essential for growth, development, and plant adaptation to stress. Organelle stress and plant defence responses were examined here using noxy8 (nonresponding to oxylipins 8) from a series of Arabidopsis mutants. The noxy8 mutation was located at the CLPC2 gene, encoding a chloroplast chaperone of the protease complex CLP. Although its CLPC1 paralogue is considered to generate redundancy, our data reveal significant differences distinguishing CLPC2 and CLPC1 functions. As such, clpc1 mutants displayed a major defect in housekeeping chloroplast proteostasis, leading to a pronounced reduction in growth and pigment levels, enhanced accumulation of chloroplast and cytosol chaperones, and resistance to fosmidomycin. Conversely, clpc2 mutants showed severe susceptibility to lincomycin inhibition of chloroplast translation and resistance to Antimycin A inhibition of mitochondrial respiration. In the response to Pseudomonas syringae pv. tomato, clpc2 but not clpc1 mutants were resistant to bacterial infection, showing higher salicylic acid levels, defence gene expression and 9‐LOX pathway activation. Our findings suggest CLPC2 and CLPC1 functional specificity, with a preferential involvement of CLPC1 in housekeeping processes and of CLPC2 in stress responses.

2024-04-10·mBio

Structural insights into the Clp protein degradation machinery

Article

作者: Li, Danyang ; Xu, Xiaolong ; Wang, Yanhui ; Deng, Zixin ; Huang, Wei ; Long, Feng

ABSTRACT The Clp protease system is important for maintaining proteostasis in bacteria. It consists of ClpP serine proteases and an AAA+ Clp-ATPase such as ClpC1. The hexameric ATPase ClpC1 utilizes the energy of ATP binding and hydrolysis to engage, unfold, and translocate substrates into the proteolytic chamber of homo- or hetero-tetradecameric ClpP for degradation. The assembly between the hetero-tetradecameric ClpP1P2 chamber and the Clp-ATPases containing tandem ATPase domains from the same species has not been studied in depth. Here, we present cryo-EM structures of the substrate-bound ClpC1:shClpP1P2 from Streptomyces hawaiiensis , and shClpP1P2 in complex with ADEP1, a natural compound produced by S. hawaiiensis and known to cause over-activation and dysregulation of the ClpP proteolytic core chamber. Our structures provide detailed information on the shClpP1-shClpP2, shClpP2-ClpC1, and ADEP1-shClpP1/P2 interactions, reveal conformational transition of ClpC1 during the substrate translocation, and capture a rotational ATP hydrolysis mechanism likely dominated by the D1 ATPase activity of chaperones. IMPORTANCE The Clp-dependent proteolysis plays an important role in bacterial homeostasis and pathogenesis. The ClpP protease system is an effective drug target for antibacterial therapy. Streptomyces hawaiiensis can produce a class of potent acyldepsipeptide antibiotics such as ADEP1, which could affect the ClpP protease activity. Although S. hawaiiensis hosts one of the most intricate ClpP systems in nature, very little was known about its Clp protease mechanism and the impact of ADEP molecules on ClpP. The significance of our research is in dissecting the functional mechanism of the assembled Clp degradation machinery, as well as the interaction between ADEP1 and the ClpP proteolytic chamber, by solving high-resolution structures of the substrate-bound Clp system in S. hawaiiensis . The findings shed light on our understanding of the Clp-dependent proteolysis in bacteria, which will enhance the development of antimicrobial drugs targeting the Clp protease system, and help fighting against bacterial multidrug resistance.

2023-12-01·International Journal of Biological Macromolecules

Crystal structure of the N-terminal domain of MtClpC1 in complex with the anti-mycobacterial natural peptide Lassomycin

Article

作者: Jagdev, Manas K ; Mohapatra, Chinmayee ; Dandapat, Jagneshwar ; Tompa, Dharma R ; Vasudevan, Dileep ; Peoples, Aaron J ; Ling, Losee L ; Lewis, Kim

Antibiotics form our frontline therapy against disease-causing bacteria. Unfortunately, antibiotic resistance is becoming more common, threatening a future where these medications can no longer cure infections. Furthermore, the emergence of multidrug-resistant (MDR), totally drug-resistant (TDR), and extensively drug-resistant (XDR) tuberculosis has increased the urgency of discovering new therapeutic leads with unique modes of action. Some natural peptides derived from actinomycetes, such as Cyclomarin A, Lassomycin, Rufomycin I, and Ecumicin, have potent and specific bactericidal activity against Mycobacterium tuberculosis, with the specificity owing to the fact that these peptides target the ClpC1 ATPase, an essential enzyme in mycobacteria, and inhibit/activate the proteolytic activity of the ClpC1/P1/P2 complex that participates in protein homeostasis. Here, we report the high-resolution crystal structure of the N-terminal domain of ClpC1 (ClpC1 NTD) in complex with Lassomycin, showing the specific binding mode of Lassomycin. In addition, the work also compares the Lassomycin complex structure with the previously known structures of ClpC1 NTD in complex with other natural peptides such as Cyclomarin A, Rufomycin I, and Ecumicin.