揭示了调节线粒体过程的新型TRAP1-选择性抑制剂
Taylor Merfeld1, Shuxia Peng2, Bradley M Keegan1
1Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN, 46556, USA.
European journal of medicinal chemistry
|June 12, 2023
概括
研究人员开发了针对线粒体热冲击蛋白90 (TRAP1) 异型的新型抑制剂. 这些化合物选择性地降解TRAP1客户端,影响细胞代谢和线粒体功能,为癌症药物开发提供了新的途径.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 热冲击蛋白90 (Hsp90) 异型在癌症中具有不同的作用.
- 由于缺乏特定的抑制剂,对线粒体异型TRAP1的了解很少.
- 针对TRAP1提供了一种新的抗癌策略.
研究的目的:
- 开发新的TRAP1选择性抑制剂.
- 使用这些抑制剂来研究TRAP1的生物功能.
- 阐明TRAP1抑制的结构基础.
主要方法:
- 设计和合成TRAP1选择性小分子.
- 抑制剂与TRAP1.1的联合结晶.
- 基于结构的药物设计.
- 评估细胞效应,包括客户端蛋白质降解,代谢变化和线粒体功能.
主要成果:
- 开发了新的TRAP1抑制剂 (化合物35和36).
- 化合物36具有较高的TRAP1选择性 (>250倍于Grp94),具有40nM的强度.
- 抑制剂选择性降解TRAP1客户端,而不会影响细胞质Hsp90客户端或诱导热冲击反应.
- 化合物抑制了氧化酸化 (OXPHOS),将新陈代谢转移到糖解,并破坏了线粒体膜潜能.
结论:
- 选择性TRAP1抑制剂是研究TRAP1生物学的有效工具.
- 准TRAP1会影响细胞代谢和线粒体完整性.
- 这些发现支持TRAP1作为一个有前途的抗癌标.
相关概念视频
The Electron Transport Chain
17.0K
The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
17.0K
Translocation of Proteins into the Mitochondria
3.2K
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
3.2K
Mitochondrial Precursor Proteins
2.6K
Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70 chaperones are targetted to TOM20-TOM22 receptor complexes.
Most of the mitochondrial...
Most of the mitochondrial...
2.6K
Electron Transport Chain: Complex I and II
14.6K
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
14.6K
Mitochondrial Protein Sorting
4.4K
Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death. Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
4.4K
ATP Synthase: Mechanism
14.8K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
14.8K


