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对PKMYT1对WEE1的选择性抑制的结构和能量见解

Xuesen Qi¹, Guozhen Li¹, Jiahai Liu²

¹Department of Urology, The Affiliated Hospital of Weifang Medical University, Weifang Medical University, Weifang, Shandong, China.

Journal of biomolecular structure & dynamics

|June 22, 2023

概括

选择性抑制蛋白激酶,膜相关的氨酸/氨酸1 (PKMYT1) 对于癌症治疗至关重要. 分子模拟显示,静电相互作用和守门者残留物Thr187是RP-6306对PKMYT1对WEE1.1的选择性的关键.

科学领域:

生物化学生物化学
结构生物学结构生物学
计算化学计算化学

背景情况:

蛋白激酶,膜相关的氨酸/氨酸1 (PKMYT1) 是一种WEE家族激酶,调节CDK1酸化,是一种癌症治疗标.
在WEE家族中的ATP结合位点的结构相似性使选择性PKMYT1抑制剂的发展复杂化.

研究的目的:

阐明RP-6306对PKMYT1对同源WEE1激酶的结合选择性的基础分子机制.
为设计更强效和选择性的PKMYT1抑制剂提供见解.

主要方法:

分子对接模拟分子对接模拟
多个微秒长度的分子动力学 (MD) 模拟.
最终点自由能量计算

主要成果:

MD模拟和结合自由能计算证实了RP-6306.6的实验结合特异性.
结合选择性主要是由蛋白质-连接体静电相互作用的差异驱动的.
非保存的守门者残留物 (PKMYT1中的Thr187与WEE1中的Asn376) 被确定为对选择性的关键.
在PKMYT1复合体中观察到RP-6306和Gly191之间的独特的水中介键,在WEE1复合体中没有.

结论:

这项研究澄清了RP-6306选择性抑制PKMYT1.1.的分子基础.
了解静电相互作用和守门者残留物的作用,可以指导下一代PKMYT1抑制剂用于癌症治疗的开发.

关键词:

在PKMYT1中,PKMYT1是PKMYT1.在WEE1中,WEE1是WEE1的代名词.有约束力的自由能源.门卫者残留物门卫者残留物分子动力学模拟的模拟.

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