近日，中国科学技术大学王雪娟及其研究小组揭示了人ATR-ATRIP的分子结构及抑制机制。相关论文于2025年5月6日发表于国际顶尖学术期刊《科学通报》杂志上。

课题组在目前处于II期临床试验的两种ATR抑制剂VE-822和RP-3500存在的情况下，确定了人ATR-ATRIP复合物的冷冻电镜结构，获得了大约3°的总分辨率。这些结构产生了一个接近完整的ATR-ATRIP复合物的原子模型，揭示了亚基化学计量学、分子内和分子间相互作用，以及包括PIKK调节域（PRD）插入在内的关键调控位点。结构比较提供了对ATR抑制剂的作用模式和选择性的见解。VE-822和RP-3500在溶剂侧附近和后囊区结合方式的不同，特别是结合方向的不同，导致活性位点的构象变化不同。令人惊讶的是，一个ATR-ATRIP复合物与VE-822分子结合，其中两个在ATR活性位点，两个在ATR-ATR二聚体界面。RP-3500的结合和选择性取决于两个结合水分子，这两个结合水的取代可能进一步增强其结合和选择性。他们的研究为理解ATR调控提供了一个结构框架，并有望协助未来针对ATR的合理药物设计。

据介绍，共济失调毛细血管扩张突变和Rad3相关（ATR）激酶是人类DNA损伤反应和复制应激的主要调节因子。靶向ATR是肿瘤药物开发的重点，目前有许多有效的、选择性的ATR抑制剂正在临床开发中。

附：英文原文

Title: Molecular architecture and inhibition mechanism of human ATR-ATRIP

Author: Gang Cai a b, Xuejuan Wang a b

Issue&Volume: 2025/05/06

Abstract: The ataxia telangiectasia–mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans. Targeting ATR is the focus of oncology drug pipelines with a number of potent, selective ATR inhibitors currently in clinical development. Here, we determined the cryo-EM structures of the human ATR-ATRIP complex in the presence of VE-822 and RP-3500, two ATR inhibitors currently in Phase II clinical trials, achieving an overall resolution of approximately 3. These structures yield a near-complete atomic model of the ATR-ATRIP complex, revealing subunit stoichiometry, intramolecular and intermolecular interactions, and critical regulatory sites including an insertion in the PIKK regulatory domain (PRD). Structural comparison provides insights into the modes of action and selectivity of ATR inhibitors. The divergent binding modes near the solvent side and in the rear pocket area of VE-822 and RP-3500, particularly their disparate binding orientations, lead to varying conformational changes in the active site. Surprisingly, one ATR-ATRIP complex binds four VE-822 molecules, with two in the ATR active site and two at the ATR-ATR dimer interface. The binding and selectivity of RP-3500 depend on two bound water molecules, which may be further enhanced by the substitution of these bound waters. Our study provides a structural framework for understanding ATR regulation and holds promise for assisting future efforts in rational drug design targeting ATR.

DOI: 10.1016/j.scib.2025.05.009

Source: https://www.sciencedirect.com/science/article/abs/pii/S209592732500489X