Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors.
Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors.
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DOI：
10.7554/elife.64691
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发表时间：
2021-03-04
期刊：
影响因子：
7.7
通讯作者：
Burke JE
中科院分区：
文献类型：
--
作者：
Rathinaswamy MK;Gaieb Z;Fleming KD;Borsari C;Harris NJ;Moeller BE;Wymann MP;Amaro RE;Burke JE
I类磷脂酰肌醇3-激酶(PI3K)是细胞功能的主要调节因子，Ib类PI3K催化亚基(p110γ)在免疫信号转导中起关键作用。P110γ是炎症性疾病的关键因子，由于其免疫调节作用，已被确定为癌症的治疗靶点。利用生化/生物物理相结合的方法，我们揭示了对激酶活性的调节，特别是定义了免疫缺陷和C末端的致癌突变如何使酶活性失活或激活。使用HDX-MS筛选抑制剂显示，激活环结合抑制剂诱导变构构象变化，类似于R1021C突变体中的构象变化。对临床开发中的先进PI3K抑制剂的结构分析揭示了新的结合口袋，可用于进一步的治疗开发。总之，这项工作为控制PI3Kγ激酶活性的调控机制提供了独特的见解，并展示了PI3K亚型和突变选择性抑制剂的设计框架。
Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the class IB PI3K catalytic subunit (p110γ) playing key roles in immune signalling. p110γ is a key factor in inflammatory diseases and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall, this work provides unique insights into regulatory mechanisms that control PI3Kγ kinase activity and shows a framework for the design of PI3K isoform and mutant selective inhibitors.