6C8C

Chimeric Pol kappa RIR Rev1 C-terminal domain in complex with JHRE06

6C8C の概要

• エントリーDOI: 10.2210/pdb6c8c/pdb
• 分子名称: Chimeric protein of the Pol Kappa RIR helix and the Rev1 C-terminal domain, 8-chloro-2-[(2,4-dichlorophenyl)amino]-3-(3-methylbutanoyl)-5-nitroquinolin-4(1H)-one (3 entities in total)
• 機能のキーワード: translesion synthesis, dna damage tolerance, rev1, replication
• 由来する生物種: Mus musculus (Mouse); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28004.39

構造登録者

Najeeb, J.,Zhou, P. (登録日: 2018-01-24, 公開日: 2019-06-12, 最終更新日: 2023-10-04)

主引用文献

Wojtaszek, J.L.,Chatterjee, N.,Najeeb, J.,Ramos, A.,Lee, M.,Bian, K.,Xue, J.Y.,Fenton, B.A.,Park, H.,Li, D.,Hemann, M.T.,Hong, J.,Walker, G.C.,Zhou, P.
A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy.
Cell, 178:152-, 2019

PubMed Abstract: Intrinsic and acquired drug resistance and induction of secondary malignancies limit successful chemotherapy. Because mutagenic translesion synthesis (TLS) contributes to chemoresistance as well as treatment-induced mutations, targeting TLS is an attractive avenue for improving chemotherapeutics. However, development of small molecules with high specificity and in vivo efficacy for mutagenic TLS has been challenging. Here, we report the discovery of a small-molecule inhibitor, JH-RE-06, that disrupts mutagenic TLS by preventing recruitment of mutagenic POL ζ. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL ζ. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL ζ recruitment. JH-RE-06 inhibits mutagenic TLS and enhances cisplatin-induced toxicity in cultured human and mouse cell lines. Co-administration of JH-RE-06 with cisplatin suppresses the growth of xenograft human melanomas in mice, establishing a framework for developing TLS inhibitors as a novel class of chemotherapy adjuvants.

PubMed: 31178121
DOI: 10.1016/j.cell.2019.05.028

実験手法

X-RAY DIFFRACTION (1.5 Å)