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分子动力学揭示了Belzutifan和HIF-2与自然变异G323E或T324的近位酸化之间的改变相互作用

Vishva Natarajan¹, Vardhan Satalkar¹, James C Gumbart²

¹School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.

|September 16, 2024

概括

·希佩尔·林道氏病通过HIF-2α驱动癌症. 贝尔祖提凡针对HIF-2α,但G323E和pT324等变体可能通过改变药物结合部位的灵活性和亲和力而导致耐药性.

科学领域:

生物化学生物化学
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

·希佩尔·林道 (VHL) 病与缺氧独立的HIF-2α积累有关,导致细胞癌等癌症.
贝尔祖提凡是一种FDA批准的药物,可抑制HIF-2α:ARNT转录活性,对VHL依赖性癌症至关重要.
自然存在的HIF-2α变体 (G323E) 和翻译后修饰 (pT324) 可能会对贝尔祖提凡产生耐药性,但机制尚不清楚.

研究的目的:

阐明G323E变异和T324酸化 (pT324) 影响贝尔祖提凡与HIF-2α:ARNT复合体结合的分子机制.
为了比较G323E和pT324对贝尔祖提凡的结构动力学和结合亲和力的不同影响.

主要方法:

用分子动力学 (MD) 模拟来分析具有 G323E 和 pT324 修饰的 belzutifan 结合-HIF-2α:ARNT 复合物.
集成机器学习被用来识别受这些修改影响的链际残留相互作用.

主要成果:

G323E和pT324都增加了贝尔祖提结合部位的结构灵活性,降低了明显的结合亲和力.
G323E的影响局限于HIF-2α PAS-B域中的Fα螺旋.
pT324降低了贝尔祖提凡的结合亲和力,并通过PAS-B和PAS-A域之间的极性相互作用稳定了HIF-2异构体,这表明它具有全效应.

结论:

这项研究揭示了G323E介导的对贝尔祖提凡抗性的分子基础.
在T324的酸化也可能通过HIF-2药物结合的全调节影响贝尔祖提凡的疗效.
这些发现对于理解和潜在地克服VHL相关癌症的耐药性至关重要.

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