Structural insight into inhibition of REV7 protein interaction revealed by docking, molecular dynamics and MM/PBSA studies. Issue 44 (24th May 2017)

• Record Type: Journal Article
• Authors: Ren, Xiaodong; Zeng, Rui; Wang, Changwei; Zhang, Mingming; Liang, Chengyuan; Tang, Zhonghai; Ren, Jinfeng
• Is Part Of: RSC advances. Volume 7:Issue 44(2017)
• Page Start: 27780
• Page End: 27786
• Publication Date: 2017-05-24
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c7ra03716c
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : The inhibitors of the REV7/REV3L protein interaction bind to the two pockets of REV7 divided by the 'safety-belt' structure, as revealed by computational modeling. Abstract : In mammalian cells, DNA polymerase ζ (Pol ζ) catalyzes the TLS step of ICLR. By acting simultaneously with Y-family DNA polymerase, Pol ζ completes replication of damaged DNA without removing the damage by inserting a nucleotide opposite the lesion. It has been demonstrated that Pol ζ represents a promising target for the treatment of chemotherapy-resistant tumors. The first series of small-molecule inhibitors targeting REV7/REV3L interaction have been identified recently, however, their corresponding binding mechanism is not known. Herein, we performed docking, molecular dynamics and MM/PBSA free energy calculations to study the binding mechanism of REV7 and its inhibitors. It was demonstrated that inhibitors bind to the two pockets divided by the 'safety-belt' structure of REV7, which was supported by the MD simulation. In addition, 2-methylfuran is an important group with an appropriate size to form the stable complex, and hydrophobic contacts were mainly responsible for stable complex formation as revealed by free energy calculation.