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Updated: Jul 6, 2025

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使用蛋白组学和基于结构的建模,用于RTKs的TAM家族的新基质预测

Naomi E Widstrom¹, Grigorii V Andrianov², Jason L Heier¹

¹Department of Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, United States.

ACS chemical biology

|December 30, 2023

概括

研究人员为TAM激酶 (Tyro3,Axel,Mer) 设计了合成基质,以帮助抑制剂的开发. 使用AlphaFold2的结构建模准确预测了激酶-基质相互作用,验证了新基质.

科学领域:

生物化学生物化学
分子生物学分子生物学
结构生物学结构生物学

背景情况:

受体氨酸激酶 (Tyro3,Axl,Mer) 的TAM家族在各种瘤信号通路中发挥作用.
目前,没有FDA批准的向TAM激酶的小分子抑制剂,阻碍了药物开发.
有效的抑制剂设计和选需要强大的工具来研究激酶活性和基质特异性.

研究的目的:

通过设计新型合成基质来解决TAM激酶研究工具的缺乏.
为了描述 Tyro3, Axl 和 Mer 激酶的基质配置.
验证使用计算建模,特别是AlphaFold2,来预测酶-基质相互作用.

主要方法:

采用了体外光蛋白学工作流程来识别TAM激酶基底基因.
使用数据处理管道 (KINATEST-ID) 来生成位置特定的评分矩阵.
使用LC-MS测量酸化率的合成和生物化学特征候选基质.
应用AlphaFold2的多分子建模来预测活性部位的激酶相互作用.

主要成果:

成功设计和合成了 Tyro3, Axl 和 Mer 激酶的新型合成基质.
生物化学分析证实了合成的酸化由他们的目标TAM激酶.
具有催化能力的激酶相互作用的AlphaFold2预测与实验验证的基质有很强的相关性.
证明了AlphaFold2在预测与激酶活性相关的-蛋白相互作用方面的实用性.

结论:

通过将偏好动机分析与结构建模相结合,可以有效地实现激酶基质设计.
这项研究首次证明了AlphaFold2在模拟蛋白相互作用以预测催化活性方面的能力.
开发的合成基质和验证的计算方法为未来的TAM激酶抑制剂研发提供了宝贵的工具.

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