PDBsum entry 6c8c

Replication

PDB id: 6c8c

Contents

Protein chains

119 a.a.

Ligands

EQ7

Waters ×428

PDB id:

6c8c

Name:

Replication

Title:

Chimeric pol kappa rir rev1 c-terminal domain in complex with jhre06

Structure:

Chimeric protein of the pol kappa rir helix and the rev1 c- terminal domain. Chain: a, b. Synonym: dinb protein,dinp,rev1-like terminal deoxycytidyl transferase. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: polk, dinb1, rev1, rev1l. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.50Å R-factor: 0.165 R-free: 0.191

Authors:

J.Najeeb,P.Zhou

Key ref:

J.L.Wojtaszek et al. (2019). A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy. Cell, 178, 152. PubMed id: 31178121 DOI: 10.1016/j.cell.2019.05.028

Date:

24-Jan-18 Release date: 12-Jun-19

Protein chains

Q920Q2  (REV1_MOUSE) -  DNA repair protein REV1 from Mus musculus

Seq: 1249 a.a.

Struc: 119 a.a.*

Protein chains

Q9QUG2  (POLK_MOUSE) -  DNA polymerase kappa from Mus musculus

Seq: 852 a.a.

Struc: 119 a.a.*

* PDB and UniProt seqs differ at 115 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.- - ?????
• Enzyme class 2: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.cell.2019.05.028

Cell 178:152 (2019)

PubMed id: 31178121

A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy.

J.L.Wojtaszek, N.Chatterjee, J.Najeeb, A.Ramos, M.Lee, K.Bian, J.Y.Xue, B.A.Fenton, H.Park, D.Li, M.T.Hemann, J.Hong, G.C.Walker, P.Zhou.

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.