蛋白酸酶5-招募基因组加速细胞灭绝-信号调控基因酶1脱化与抗增殖活性
Qiuyue Zhang1,2, Xuexuan Wu1,2, Hengheng Zhang1,2
1State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Journal of the American Chemical Society
|December 22, 2022
概括
研究人员开发了DDO3711,一种新型的木乃伊,可以调用PP5去化p-ASK1 ((T838),有效地减少胃癌的进展. 这种有针对性的方法有望调节异常化蛋白.
科学领域:
- 分子生物学
- 癌症学
- 生物化学
背景情况:
- 异常的蛋白质酸化,特别是像ASK1这样的基蛋白的高酸化,驱动癌症的进展.
- PP5通常去化p-ASK1 ((T838),但其活性在瘤中受到抑制,导致p-ASK1 ((T838) 水平升高.
- 针对蛋白质脱化提供了癌症治疗的策略.
研究的目的:
- 设计和验证酸酶招募基因组 (PHORC) 用于p-ASK1的化.
- 通过恢复ASK1酸化平衡来开发胃癌的新疗法.
主要方法:
- DDO3711的设计,PHORC包括一个与PP5激活器连接的ASK1抑制剂.
- 在体外和体内实验中评估DDO3711降低p-ASK1 (T838) 水平的有效性.
- 使用MKN45胃癌细胞进行抗增殖活性测定.
主要成果:
- 在体外和体内,DDO3711有效降低了p-ASK1 (T838) 的水平.
- DDO3711通过直接结合和靠近介导的机制对MKN45细胞表现出显著的抗增殖活性 (IC50=0. 5μM).
- 单独或组合的ASK1抑制剂和PP5激活剂都没有对MKN45细胞产生影响,这凸显了PHORC结构的必要性.
结论:
- 以DDO3711为例的PHORC是加速向蛋白质脱的有效工具.
- 这种方法为蛋白的精确酸化调节提供了一种新的策略.
- 这些发现支持PHORCs在开发由异常化驱动的癌症新疗法的潜力.
相关概念视频
Amplifying Signals via Enzymatic Cascade
8.6K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.6K
PI3K/mTOR/AKT Signaling Pathway
3.8K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.8K
The JAK-STAT Signaling Pathway
9.1K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
9.1K
Interactions Between Signaling Pathways
6.4K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.4K
Protein Kinases and Phosphatases
13.3K
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
13.3K
mTOR Signaling and Cancer Progression
3.9K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.9K


