9bp9: Difference between revisions
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The | ==Human DNA polymerase theta helicase domain in complex with inhibitor AB25583, dimer form== | ||
<StructureSection load='9bp9' size='340' side='right'caption='[[9bp9]], [[Resolution|resolution]] 3.21Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9bp9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9BP9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9BP9 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.21Å</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=9bp9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9bp9 OCA], [https://pdbe.org/9bp9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9bp9 RCSB], [https://www.ebi.ac.uk/pdbsum/9bp9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9bp9 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 a DNA helicase-polymerase protein that facilitates DNA repair and is synthetic lethal with homology-directed repair (HDR) factors. Thus, Poltheta is a promising precision oncology drug-target in HDR-deficient cancers. Here, we characterize the binding and mechanism of action of a Poltheta helicase (Poltheta-hel) small-molecule inhibitor (AB25583) using cryo-EM. AB25583 exhibits 6 nM IC(50) against Poltheta-hel, selectively kills BRCA1/2-deficient cells, and acts synergistically with olaparib in cancer cells harboring pathogenic BRCA1/2 mutations. Cryo-EM uncovers predominantly dimeric Poltheta-hel:AB25583 complex structures at 3.0-3.2 A. The structures reveal a binding-pocket deep inside the helicase central-channel, which underscores the high specificity and potency of AB25583. The cryo-EM structures in conjunction with biochemical data indicate that AB25583 inhibits the ATPase activity of Poltheta-hel helicase via an allosteric mechanism. These detailed structural data and insights about AB25583 inhibition pave the way for accelerating drug development targeting Poltheta-hel in HDR-deficient cancers. | |||
Structural basis for a Poltheta helicase small-molecule inhibitor revealed by cryo-EM.,Ito F, Li Z, Minakhin L, Chandramouly G, Tyagi M, Betsch R, Krais JJ, Taberi B, Vekariya U, Calbert M, Skorski T, Johnson N, Chen XS, Pomerantz RT Nat Commun. 2024 Aug 14;15(1):7003. doi: 10.1038/s41467-024-51351-4. PMID:39143110<ref>PMID:39143110</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9bp9" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Chen XS]] | |||
[[Category: Ito F]] | |||
[[Category: Li Z]] | |||
Latest revision as of 08:25, 28 August 2024
Human DNA polymerase theta helicase domain in complex with inhibitor AB25583, dimer formHuman DNA polymerase theta helicase domain in complex with inhibitor AB25583, dimer form
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 a DNA helicase-polymerase protein that facilitates DNA repair and is synthetic lethal with homology-directed repair (HDR) factors. Thus, Poltheta is a promising precision oncology drug-target in HDR-deficient cancers. Here, we characterize the binding and mechanism of action of a Poltheta helicase (Poltheta-hel) small-molecule inhibitor (AB25583) using cryo-EM. AB25583 exhibits 6 nM IC(50) against Poltheta-hel, selectively kills BRCA1/2-deficient cells, and acts synergistically with olaparib in cancer cells harboring pathogenic BRCA1/2 mutations. Cryo-EM uncovers predominantly dimeric Poltheta-hel:AB25583 complex structures at 3.0-3.2 A. The structures reveal a binding-pocket deep inside the helicase central-channel, which underscores the high specificity and potency of AB25583. The cryo-EM structures in conjunction with biochemical data indicate that AB25583 inhibits the ATPase activity of Poltheta-hel helicase via an allosteric mechanism. These detailed structural data and insights about AB25583 inhibition pave the way for accelerating drug development targeting Poltheta-hel in HDR-deficient cancers. Structural basis for a Poltheta helicase small-molecule inhibitor revealed by cryo-EM.,Ito F, Li Z, Minakhin L, Chandramouly G, Tyagi M, Betsch R, Krais JJ, Taberi B, Vekariya U, Calbert M, Skorski T, Johnson N, Chen XS, Pomerantz RT Nat Commun. 2024 Aug 14;15(1):7003. doi: 10.1038/s41467-024-51351-4. PMID:39143110[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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