|
|
| (One intermediate revision not shown.) |
| Line 3: |
Line 3: |
| | <StructureSection load='6c8c' size='340' side='right'caption='[[6c8c]], [[Resolution|resolution]] 1.50Å' scene=''> | | <StructureSection load='6c8c' size='340' side='right'caption='[[6c8c]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == 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 [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. 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 [https://proteopedia.org/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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5Å</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> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6c8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c8c OCA], [https://pdbe.org/6c8c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6c8c RCSB], [https://www.ebi.ac.uk/pdbsum/6c8c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6c8c ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/POLK_MOUSE 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).<ref>PMID:12432099</ref> | + | [https://www.uniprot.org/uniprot/POLK_MOUSE 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).<ref>PMID:12432099</ref> [https://www.uniprot.org/uniprot/REV1_MOUSE REV1_MOUSE] Deoxycytidyl transferase involved in DNA repair. Transfers a dCMP residue from dCTP to the 3'-end of a DNA primer in a template-dependent reaction. May assist in the first step in the bypass of abasic lesions by the insertion of a nucleotide opposite the lesion. Required for normal induction of mutations by physical and chemical agents.<ref>PMID:11711549</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 23: |
Line 24: |
| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Najeeb, J]] | + | [[Category: Mus musculus]] |
| - | [[Category: Zhou, P]] | + | [[Category: Najeeb J]] |
| - | [[Category: Dna damage tolerance]] | + | [[Category: Zhou P]] |
| - | [[Category: Replication]]
| + | |
| - | [[Category: Rev1]]
| + | |
| - | [[Category: Translesion synthesis]]
| + | |
| Structural highlights
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] REV1_MOUSE Deoxycytidyl transferase involved in DNA repair. Transfers a dCMP residue from dCTP to the 3'-end of a DNA primer in a template-dependent reaction. May assist in the first step in the bypass of abasic lesions by the insertion of a nucleotide opposite the lesion. Required for normal induction of mutations by physical and chemical agents.[2]
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[3]
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
- ↑ Masuda Y, Takahashi M, Fukuda S, Sumii M, Kamiya K. Mechanisms of dCMP transferase reactions catalyzed by mouse Rev1 protein. J Biol Chem. 2002 Jan 25;277(4):3040-6. Epub 2001 Nov 15. PMID:11711549 doi:10.1074/jbc.M110149200
- ↑ 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
|
