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碳足迹指导了基因编码的近距离反应性蛋白质结合物的设计

Hui Ye¹, Yinxue Zhu², Ying Kong²

¹Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang No. 24, Nanjing 210009, Jiangsu, China.

Analytical chemistry

|April 29, 2024

概括

这项研究引入了一种新的足迹指导的基因编码共价结合剂 (足迹-GECB) 方法. 这种方法使用碳足迹来识别非天然氨基酸的部位,使得无需晶体学,可用共价蛋白质结合剂.

科学领域:

生物化学生物化学
化学生物学化学生物学
结构生物学结构生物学

背景情况:

基因编码近位反应性非自然氨基酸 (PrUaas) 允许蛋白质对相互作用伙伴进行共聚结合,从而可能阻止不必要的相互作用.
确定最佳的PrUaa点是关键的,但具有挑战性,通常依赖于晶体学.

研究的目的:

开发一种新的方法来识别无需晶体学的PrUaa点.
为治疗和研究应用设计具有共价结合能力的蛋白质.

主要方法:

开发了一种指导足迹的基因编码共价结合剂 (足迹-GECB) 方法.
利用碳足迹,一个质谱技术,以确定蛋白质-蛋白质相互作用地点.
将遗传编码的PrUaas,如硫酸-l-氨酸 (FSY),转化为已识别的响应残留物.

主要成果:

通过使用足迹引导的FSY整合,成功设计了KRAS变体,可以不可逆转地绑定RAF1.
通过针对RAF1中的响应性位点,即使没有晶体结构数据,也为瘤性KRAS^G12D创建了共价结合剂.
证明了碳烯足迹在指导蛋白质-蛋白质相互作用中的PrUaa定作用的有效性.

结论:

足迹-GECB方法扩展了对蛋白质-蛋白质相互作用 (PPI) 的共价蛋白质结合剂的设计.
这种方法为开发PPI抑制剂提供了一个结晶学独立的策略.
该方法支持基础研究和新型生物治疗药物的开发.

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