人类阿拉基酸12S-氧酶结合内源和外源抑制剂的冷-EM结构
Jesse I Mobbs1,2, Katrina A Black3,4,5, Michelle Tran6
1Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
Blood
|July 28, 2023
概括
对人类12-氧酶 (12-LOX) 的结构洞察力揭示了其多重的寡合体状态和构造. 对12-LOX组合,催化和抑制剂结合的这种理解有助于在治疗诸如肝素诱导的血小板衰竭等疾病的药物发现.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 人类12-氧基酶 (12-LOX) 对于血小板激活至关重要,也是肝素诱导的血小板缩的治疗点.
- 了解12-LOX机制和结构是有限的,阻碍了药物发现.
研究的目的:
- 使用冷电子显微镜确定人类12-LOX的高分辨率结构.
- 为了阐明酶的寡合状态,构造和小分子相互作用.
主要方法:
- 单粒子冷电子显微镜 (cryo-EM) 在1.7-2.8 Å分辨率.
- 分析人类的12-LOX寡合化,形状动态和连接物结合.
主要成果:
- 12-LOX存在于单体到六合体状态,影响催化活性和膜协会.
- 确定了代表催化循环阶段的独特的二元体构造.
- 观察到内源性抑制剂 (acyl-CoA) 和外源性抑制剂 (ML355) 与各种寡合体的结合.
结论:
- 对12-LOX寡合体组合,催化机制和小分子结合的新见解.
- 结构数据为开发针对12-LOX的新药提供了基础.
- 研究结果支持使用12-LOX作为治疗肝素诱导的血小板缺血的标.
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