自组装的小分子形成纳米纤维,结合procaspase-3以促进激活
Julie A Zorn1, Holger Wille, Dennis W Wolan
1Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
Journal of the American Chemical Society
|November 10, 2011
概括
小分子1541自组装成纳米纤维,作为一种新的生物催化材料. 这些纤维通过诱导的近距离激活 procaspase-3 (一种酶前体),提供新的药物发现途径.
科学领域:
- 生物化学 生物化学
- 生物物理学的生物物理.
- 药物发现 药物发现 药物发现
背景情况:
- 小分子可以调节酶功能,为药物发现和全调节提供抑制剂的替代品.
- 之前确定的一种化合物,1541被发现可以通过高通量选 (HTS) 刺激procaspase-3的激活到成熟的caspase-3.
研究的目的:
- 为了研究化合物1541激活 prokaspase-3 的机制.
- 描述化合物1541的自我组装特性及其作为生物催化材料的功能.
主要方法:
- 高通量选 (HTS) 用于识别1541.1化合物.
- 1541自组装成纳米纤维的特征.
- 测试以确定由1541纳米纤维细胞激活公酶-3的机制.
主要成果:
- 化合物1541自组装成长于1微米的纳米纤维.
- 与典型的球状蛋白质聚合器相比,这些纳米纤维具有独特的特性.
- 1541纳米纤维通过诱导的近距离机制激活 procaspase-3,作为生物催化材料.
结论:
- 小分子自我组装成纳米纤维提供了一个新的平台,用于proenzyme激活.
- 这种纤维介导的激活机制可能会模仿蛋白质支架上的自然代谢酶处理.
- 这些发现为开发药物发现和全调节的激活剂开辟了新的途径.
相关概念视频
Caspases
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
The Extrinsic Apoptotic Pathway
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Phagocytosis of Apoptotic Cells
Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or immature dendritic cells. Non-professional phagocytes such as epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes.
Normal cells contain receptors that prevent them from being recognized by phagocytes.
Normal cells contain receptors that prevent them from being recognized by phagocytes.
Apoptosis
Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.
Protein Complex Assembly
Proteins can form homomeric complexes with another unit of the same protein or heteromeric complexes with different types. Most protein complexes self-assemble spontaneously via ordered pathways, while some proteins need assembly factors that guide their proper assembly. Despite the crowded intracellular environment, proteins usually interact with their correct partners and form functional complexes.
Many viruses self-assemble into a fully functional unit using the infected host cell to...
Many viruses self-assemble into a fully functional unit using the infected host cell to...


