Yuan Longxiao, Liang Xiaodan, He Lei
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300353, China.
School of Computer Sciences and Technology, Tiangong University, Tianjin 300387, China.
ACS Omega. 2024 May 2;9(19):20819-20831. doi: 10.1021/acsomega.3c09433. eCollection 2024 May 14.
DNA topoisomerase 2-binding protein 1 (Topbp1) plays a crucial role in activating the ataxia-telangiectasia mutated and rad3-related (ATR) complex to initiate DNA damage repair responses. For this process to occur, it is necessary for PHF8 to dissociate from Topbp1. Topbp1 binds to the acidic patch sequence (APS) of PHF8 through its C-terminal BRCT7/8 domain, and disrupting this interaction could be a promising strategy for cancer treatment. To investigate the dissociation process and binding pattern of BRCT7/8-PHF8, we employed enhanced sampling techniques, such as steered molecular dynamics (SMD) simulations and accelerated molecular dynamics (aMD) simulations, along with self-organizing maps (SOM) and time-resolved force distribution analysis (TRFDA) methodologies. Our results demonstrate that the dissociation of PHF8 from BRCT7/8 starts from the N-terminus, leading to the unfolding of the N-terminal helix. Additionally, we identified critical residues that play a pivotal role in this dissociation process. These findings provide valuable insights into the disassociation of PHF8 from BRCT7/8, which could potentially guide the development of novel drugs targeting Topbp1 for cancer therapy.
DNA拓扑异构酶2结合蛋白1（Topbp1）在激活共济失调毛细血管扩张症突变和rad3相关（ATR）复合物以启动DNA损伤修复反应中起关键作用。为了使这个过程发生，PHF8从Topbp1解离是必要的。Topbp1通过其C端BRCT7/8结构域与PHF8的酸性补丁序列（APS）结合，破坏这种相互作用可能是一种很有前景的癌症治疗策略。为了研究BRCT7/8与PHF8的解离过程和结合模式，我们采用了增强采样技术，如引导分子动力学（SMD）模拟和加速分子动力学（aMD）模拟，以及自组织映射（SOM）和时间分辨力分布分析（TRFDA）方法。我们的结果表明，PHF8从BRCT7/8的解离从N端开始，导致N端螺旋展开。此外，我们确定了在这个解离过程中起关键作用的关键残基。这些发现为PHF8从BRCT7/8的解离提供了有价值的见解，这可能潜在地指导针对Topbp1的新型癌症治疗药物的开发。
