Insights into the Dissociation Process and Binding Pattern of the BRCT7/8-PHF8 Complex

Longxiao Yuan; Xiaodan Liang; Lei He

doi:10.1021/acsomega.3c09433

Insights into the Dissociation Process and Binding Pattern of the BRCT7/8-PHF8 Complex

ACS Omega. 2024 May 2;9(19):20819-20831. doi: 10.1021/acsomega.3c09433. eCollection 2024 May 14.

Authors

Longxiao Yuan¹, Xiaodan Liang², Lei He³

Affiliations

¹ State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300353, China.
² School of Computer Sciences and Technology, Tiangong University, Tianjin 300387, China.
³ Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.

Abstract

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.