更新于：2024-11-01

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

更新于：2024-11-01

基本信息

关联

项与 ATP 依赖性蛋白酶 ATP 结合亚基 ClpC2 x ATP 依赖性蛋白酶 ATP 结合亚基 ClpC1 相关的药物

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

100 项与 ATP 依赖性蛋白酶 ATP 结合亚基 ClpC2 x 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 ClpC2 x 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 ClpC2 x 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 ClpC2 x 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.

2023-05-01·Cell1区 · 生物学

Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival

1区 · 生物学

Article

作者: Schwechel, Kristin ; Kalscheuer, Rainer ; Guha, Somraj ; Kleine, Stefan ; Hartl, Markus ; Kaiser, Markus ; Payne, Richard J. ; Meinhart, Anton ; Clausen, Tim ; Weinstabl, Harald ; Kaschani, Farnusch ; Morreale, Francesca Ester ; Junker, Sabryna ; Schmiedel, Volker M. ; Fischel, Katharina ; Junk, Lukas ; van Geelen, Lasse ; Boehmelt, Guido ; Rumpel, Klaus ; Hawkins, Paige M. E. ; Kazmaier, Uli ; Leodolter, Julia ; Hoi, David M. ; Podlesainski, David

The ClpC1:ClpP1P2 protease is a core component of the proteostasis system in mycobacteria.To improve the efficacy of antitubercular agents targeting the Clp protease, we characterized the mechanism of the antibiotics cyclomarin A and ecumicin.Quant. proteomics revealed that the antibiotics cause massive proteome imbalances, including upregulation of two unannotated yet conserved stress response factors, ClpC2 and ClpC3.These proteins likely protect the Clp protease from excessive amounts of misfolded proteins or from cyclomarin A, which we show to mimic damaged proteins.To overcome the Clp security system, we developed a BacPROTAC that induces degradation of ClpC1 together with its ClpC2 caretaker.The dual Clp degrader, built from linked cyclomarin A heads, was highly efficient in killing pathogenic Mycobacterium tuberculosis, with >100-fold increased potency over the parent antibiotic.Together, our data reveal Clp scavenger proteins as important proteostasis safeguards and highlight the potential of BacPROTACs as future antibiotics.

2023-03-21·Communications biology

ClpC2 protects mycobacteria against a natural antibiotic targeting ClpC1-dependent protein degradation.

Article

作者: Taylor, Gabrielle ; Weber-Ban, Eilika ; Cui, Hengjun ; Leodolter, Julia ; Giese, Christoph

Mycobacterium tuberculosis Clp proteases are targeted by several antitubercular compounds, including cyclomarin A (CymA). CymA exerts its toxicity by binding to AAA + chaperone ClpC1. Here, we show that CymA can also bind a partial homologue of ClpC1, known as ClpC2, and we reveal the molecular basis of these interactions by determining the structure of the M. tuberculosis ClpC2:CymA complex. Furthermore, we show deletion of clpC2 in Mycobacterium smegmatis increases sensitivity to CymA. We find CymA exposure leads to a considerable upregulation of ClpC2 via a mechanism in which binding of CymA to ClpC2 prevents binding of ClpC2 to its own promoter, resulting in upregulation of its own transcription in response to CymA. Our study reveals that ClpC2 not only senses CymA, but that through this interaction it can act as a molecular sponge to counteract the toxic effects of CymA and possibly other toxins targeting essential protease component ClpC1 in mycobacteria.