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针对PTPN22在非orthosteric结合部位A片段方法的向

Paola Di Lello¹, Marta M Wells², Ben Davis³

¹Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.

|January 26, 2026

概括

研究人员确定了PTPN22酸酶的新型非orthosteric配体,PTPN22酸酶是T细胞信号传导的关键调节器. 这一发现提供了针对PTPN22的新策略,可能会影响癌症免疫疗法和自身免疫性疾病.

科学领域:

生物化学生物化学
免疫学免疫学免疫学
药理学药理学是指药理学的学科.

背景情况:

蛋白氨酸酸酶非受体类型22 (PTPN22) 是T细胞受体信号的关键负调节器.
一种特定的变异,PTPN22 (C1858T),在接受抗PD-L1治疗的患者中显示出与降低癌症风险和改善存活率的关联,这表明它在瘤免疫力中起作用.
由于保留了活性位点,向酸酶具有挑战性,因此需要探索非正向性结合位点.

研究的目的:

开发一种用于发现和表征PTPN22酸酶域的非orthosteric配体的策略.
通过全性机制识别调节PTPN22活性的新型小分子.

主要方法:

采用片段选方法来识别PTPN22的潜在配体.
使用了一种多学科的表征策略,将实验数据与分子动力学模拟集成在一起,当共结晶失败时.
在PTPN22酸酶域上的两个以前未识别的nonorthosteric位点证实了联结结合.

主要成果:

在两个新的非orthosteric位点识别和推进与PTPN22结合的片段.
通过综合实验和计算方法成功表征这些连接体.
通过非orthosteric调制来针对PTPN22的可行策略的演示.

结论:

该研究成功地确定了PTPN22的新型非正经结合性结合位和结合体.
这种方法为开发针对PTPN22的治疗方法提供了有希望的途径,可能用于癌症免疫疗法和自身免疫性疾病.
这些发现突显了向酸酶中的全位的潜力,利用保存的结构特征.

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