结合一个共同的抑制剂的细菌和人类基糖转移酶的结构告知了选择性治疗方法
Beebee Yusrah Kaudeer1, Jacob M Kirsh1, Katsuhiko Mitachi2
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
研究人员开发了APPB,它是一种强大的抑制剂,向MraY和DPAGT1酶,对细菌和癌细胞过程至关重要. 低温-EM结构揭示了抑制剂构造,指导了新的抗菌和抗癌药物的设计.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 葡萄糖合物对生物过程至关重要,由葡萄糖转移酶合成.
- MraY和DPAGT1分别是细菌peptidoglycan和真核生物N-链 glycans 所必需的正体糖酶转移酶.
- 这些酶是开发抗菌和抗癌疗法的关键标.
研究的目的:
- 确定与抑制剂APPB结合的MraY和DPAGT1的冷EM结构.
- 为设计下一代MraY和DPAGT1特异性抑制剂提供结构性见解.
- 引导开发新型抗菌和抗癌疗法.
主要方法:
- 单粒子冷电子显微镜 (cryo-EM) 在2.9 Å分辨率.
- 生物化学测试以确定抑制剂功效 (IC50值).
- 对受抑制剂结合的骨科医生进行比较结构分析.
主要成果:
- 冷-EM结构显示了APPB与MraY和DPAGT1的结合,显示每个蛋白质有两个不同的构造.
- 抑制剂构造与中央胺碳基的局部结相互作用相关.
- 结构数据提供了关于核酸相互作用和结合点环境的具体见解.
结论:
- 该研究为开发MraY和DPAGT1特异性抑制剂提供了设计原则.
- 同时,鉴别受抑制剂结合的正义学家有助于设计选择性治疗方法.
- APPB作为下一代针对这些酶的抗菌和抗癌药物的基础.
更多相关视频
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
09:30Author Spotlight: Exploring Cellular Processes by Modeling Ligands in Cryo-EM Maps
Published on: July 19, 2024
相关概念视频
Enzyme Inhibition
Eukaryotic Transcription Inhibitors
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Enzymes
Enzyme deficiencies can often translate into life-threatening diseases. For example, a genetic abnormality resulting in the deficiency of the enzyme G6PD...
Phosphoinositides and PIPs
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Indirect-Acting Cholinergic Agonists: Mechanism of Action
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
