REV7 是一种 HORMA（Hop1、Rev7、Mad2）家族衔接蛋白，最出名的是作为跨损伤合成 (TLS) DNA 聚合酶 z (Pol z) 的辅助亚基。在这个角色中，REV7 通过将 REV7 中的 REV7 结合基序 (RBM) 锁定在 REV7 安全带环下方，来结合 REV3（Pol z 的催化亚基）。 REV7 使用相同的机制与 DNA 损伤反应 (DDR) 和有丝分裂中其他蛋白质的 RBM 相互作用。由于 REV7 对 TLS 和其他 DDR 通路的重要性，利用小分子靶向 REV7:RBM 蛋白质-蛋白质相互作用 (PPI) 已成为增强癌症对基因毒性化疗反应的策略。为了识别 REV7:RBM 界面处的可药物口袋，我们对 REV7 与几个 RBM 伙伴的复合物进行了计算分析。不同界面区域对 REV7:RBM 稳定性的贡献得到了实验证实。这些研究提供了对关键分子间相互作用的见解，并为 REV7:RBM PPI 抑制剂的设计建立了 REV7 的靶向区域。版权所有 © 2024 Elsevier Inc. 保留所有权利。

REV7 is a HORMA (Hop1, Rev7, Mad2) family adaptor protein best known as an accessory subunit of the translesion synthesis (TLS) DNA polymerase ζ (Polζ). In this role, REV7 binds REV3, the catalytic subunit of Polζ, by locking REV7-binding motifs (RBMs) in REV3 underneath the REV7 safety-belt loop. The same mechanism is used by REV7 to interact with RBMs from other proteins in DNA damage response (DDR) and mitosis. Because of the importance of REV7 for TLS and other DDR pathways, targeting REV7:RBM protein-protein interactions (PPIs) with small molecules has emerged as a strategy to enhance cancer response to genotoxic chemotherapy. To identify druggable pockets at the REV7:RBM interface, we performed computational analyses of REV7 complexed with several RBM partners. The contributions of different interface regions to REV7:RBM stabilization were corroborated experimentally. These studies provide insights into key intermolecular interactions and establish targetable regions of REV7 for the design of REV7:RBM PPI inhibitors.Copyright © 2024 Elsevier Inc. All rights reserved.