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6c8c

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Revision as of 06:16, 10 July 2019

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

Structural highlights

6c8c is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	Rev1, Rev1l (LK3 transgenic mice)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[POLK_MOUSE] DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Depending on the context, it inserts the correct base, but causes frequent base transitions, transversions and frameshifts. Lacks 3'-5' proofreading exonuclease activity. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity (By similarity).^[1]

Publication Abstract from PubMed

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 zeta. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL zeta. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL zeta 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.

A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy.,Wojtaszek JL, Chatterjee N, Najeeb J, Ramos A, Lee M, Bian K, Xue JY, Fenton BA, Park H, Li D, Hemann MT, Hong J, Walker GC, Zhou P Cell. 2019 Jun 4. pii: S0092-8674(19)30556-2. doi: 10.1016/j.cell.2019.05.028. PMID:31178121^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ogi T, Shinkai Y, Tanaka K, Ohmori H. Polkappa protects mammalian cells against the lethal and mutagenic effects of benzo[a]pyrene. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15548-53. Epub 2002 Nov 13. PMID:12432099 doi:10.1073/pnas.222377899
↑ Wojtaszek JL, Chatterjee N, Najeeb J, Ramos A, Lee M, Bian K, Xue JY, Fenton BA, Park H, Li D, Hemann MT, Hong J, Walker GC, Zhou P. A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy. Cell. 2019 Jun 4. pii: S0092-8674(19)30556-2. doi: 10.1016/j.cell.2019.05.028. PMID:31178121 doi:http://dx.doi.org/10.1016/j.cell.2019.05.028

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6c8c"

@@ Line 3: / Line 3: @@
 <StructureSection load='6c8c' size='340' side='right'caption='[[6c8c]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6c8c]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C8C FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6c8c]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C8C FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EQ7:8-chloro-2-[(2,4-dichlorophenyl)amino]-3-(3-methylbutanoyl)-5-nitroquinolin-4(1H)-one'>EQ7</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Rev1, Rev1l ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6c8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c8c OCA], [http://pdbe.org/6c8c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6c8c RCSB], [http://www.ebi.ac.uk/pdbsum/6c8c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6c8c ProSAT]</span></td></tr>
 </table>
@@ Line 23: / Line 24: @@
 </StructureSection>
 [[Category: Large Structures]]
+[[Category: Lk3 transgenic mice]]
 [[Category: Najeeb, J]]
 [[Category: Zhou, P]]

6c8c

From Proteopedia

Revision as of 06:16, 10 July 2019

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

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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