6C8C

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

Summary for 6C8C

• Entry DOI: 10.2210/pdb6c8c/pdb
• Descriptor: 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)
• Functional Keywords: translesion synthesis, dna damage tolerance, rev1, replication
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 2
• Total formula weight: 28004.39

Authors

Najeeb, J.,Zhou, P. (deposition date: 2018-01-24, release date: 2019-06-12, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.5 Å)