8e23: Difference between revisions
New page: '''Unreleased structure''' The entry 8e23 is ON HOLD until Paper Publication Authors: Mader, P., Pau, V.P.T., Sicheri, F. Description: Human DNA polymerase theta in complex with allost... |
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The | ==Human DNA polymerase theta in complex with allosteric inhibitor== | ||
<StructureSection load='8e23' size='340' side='right'caption='[[8e23]], [[Resolution|resolution]] 2.59Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8e23]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8E23 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E23 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.59Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DG3:2-3-DIDEOXYGUANOSINE-5-TRIPHOSPHATE'>DG3</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=UAF:N-methyl-N-phenyl[(3aM)-3-(trifluoromethyl)cyclopenta[c]pyrazol-2(1H)-yl]ethanethioamide'>UAF</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=8e23 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e23 OCA], [https://pdbe.org/8e23 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e23 RCSB], [https://www.ebi.ac.uk/pdbsum/8e23 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e23 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DPOLQ_HUMAN DPOLQ_HUMAN] Has a DNA polymerase activity on nicked double-stranded DNA and on a singly primed DNA template. The enzyme activity is resistant to aphidicolin, and inhibited by dideoxynucleotides. Exhibites a single-stranded DNA-dependent ATPase activity. Could be involved in the repair of interstrand cross-links.<ref>PMID:14576298</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
DNA polymerase theta (Poltheta) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Poltheta (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Poltheta inhibitor that showed in vivo efficacy in an HCT116 BRCA2(-/-) mouse tumor xenograft model. | |||
Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Poltheta.,Bubenik M, Mader P, Mochirian P, Vallee F, Clark J, Truchon JF, Perryman AL, Pau V, Kurinov I, Zahn KE, Leclaire ME, Papp R, Mathieu MC, Hamel M, Duffy NM, Godbout C, Casas-Selves M, Falgueyret JP, Baruah PS, Nicolas O, Stocco R, Poirier H, Martino G, Fortin AB, Roulston A, Chefson A, Dorich S, St-Onge M, Patel P, Pellerin C, Ciblat S, Pinter T, Barabe F, El Bakkouri M, Parikh P, Gervais C, Sfeir A, Mamane Y, Morris SJ, Black WC, Sicheri F, Gallant M J Med Chem. 2022 Sep 20. doi: 10.1021/acs.jmedchem.2c00998. PMID:36126059<ref>PMID:36126059</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8e23" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
*[[DNA polymerase 3D structures|DNA polymerase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Mader P]] | |||
[[Category: Pau VPT]] | |||
[[Category: Sicheri F]] | |||
Latest revision as of 20:33, 18 October 2023
Human DNA polymerase theta in complex with allosteric inhibitorHuman DNA polymerase theta in complex with allosteric inhibitor
Structural highlights
FunctionDPOLQ_HUMAN Has a DNA polymerase activity on nicked double-stranded DNA and on a singly primed DNA template. The enzyme activity is resistant to aphidicolin, and inhibited by dideoxynucleotides. Exhibites a single-stranded DNA-dependent ATPase activity. Could be involved in the repair of interstrand cross-links.[1] Publication Abstract from PubMedDNA polymerase theta (Poltheta) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Poltheta (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Poltheta inhibitor that showed in vivo efficacy in an HCT116 BRCA2(-/-) mouse tumor xenograft model. Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Poltheta.,Bubenik M, Mader P, Mochirian P, Vallee F, Clark J, Truchon JF, Perryman AL, Pau V, Kurinov I, Zahn KE, Leclaire ME, Papp R, Mathieu MC, Hamel M, Duffy NM, Godbout C, Casas-Selves M, Falgueyret JP, Baruah PS, Nicolas O, Stocco R, Poirier H, Martino G, Fortin AB, Roulston A, Chefson A, Dorich S, St-Onge M, Patel P, Pellerin C, Ciblat S, Pinter T, Barabe F, El Bakkouri M, Parikh P, Gervais C, Sfeir A, Mamane Y, Morris SJ, Black WC, Sicheri F, Gallant M J Med Chem. 2022 Sep 20. doi: 10.1021/acs.jmedchem.2c00998. PMID:36126059[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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