7aom: Difference between revisions
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==Structure of NUDT15 in complex with Ganciclovir triphosphate== | ==Structure of NUDT15 in complex with Ganciclovir triphosphate== | ||
<StructureSection load='7aom' size='340' side='right'caption='[[7aom]]' scene=''> | <StructureSection load='7aom' size='340' side='right'caption='[[7aom]], [[Resolution|resolution]] 1.95Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AOM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AOM FirstGlance]. <br> | <table><tr><td colspan='2'>[[7aom]] 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=7AOM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AOM FirstGlance]. <br> | ||
</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=7aom FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aom OCA], [https://pdbe.org/7aom PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aom RCSB], [https://www.ebi.ac.uk/pdbsum/7aom PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aom ProSAT]</span></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]] 1.95Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=RQ2:Ganciclovir+triphosphate'>RQ2</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=7aom FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aom OCA], [https://pdbe.org/7aom PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aom RCSB], [https://www.ebi.ac.uk/pdbsum/7aom PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aom ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/NUD15_HUMAN NUD15_HUMAN] Mediates the hydrolysis of some nucleoside diphosphate derivatives. Can degrade 8-oxo-dGTP in vitro, suggesting that it may remove an oxidatively damaged form of guanine (7,8-dihydro-8-oxoguanine) from DNA and the nucleotide pool, thereby preventing misincorporation of 8-oxo-dGTP into DNA thus preventing A:T to C:G transversions. Its substrate specificity in vivo however remains unclear (By similarity). May have a role in DNA synthesis and cell cycle progression through the interaction with PCNA.<ref>PMID:19419956</ref> <ref>PMID:22556419</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Ganciclovir (GCV) is the first-line therapy against human cytomegalovirus (HCMV), a widespread infection that is particularly dangerous for immunodeficient individuals. Closely resembling deoxyguanosine triphosphate, the tri-phosphorylated metabolite of GCV (GCV-TP) is preferentially incorporated by the viral DNA polymerase, thereby terminating chain extension and, eventually, viral replication. However, the treatment outcome of GCV varies greatly among individuals, therefore warranting better understanding of its metabolism. Here we show that NUDT15, a Nudix hydrolase known to metabolize thiopurine triphosphates, can similarly hydrolyze GCV-TP through biochemical studies and co-crystallization of the NUDT15/GCV-TP complex. More critically, GCV efficacy was potentiated in HCMV-infected cells following NUDT15 depletion by RNAi or inhibition by an in-house-developed, nanomolar NUDT15 inhibitor, TH8321, suggesting that pharmacological targeting of NUDT15 is a possible avenue to improve existing anti-HCMV regimens. Collectively, the data further implicate NUDT15 as a broad-spectrum metabolic regulator of nucleoside analog therapeutics, such as thiopurines and GCV. | |||
NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir.,Zhang SM, Rehling D, Jemth AS, Throup A, Landazuri N, Almlof I, Gottmann M, Valerie NCK, Borhade SR, Wakchaure P, Page BDG, Desroses M, Homan EJ, Scobie M, Rudd SG, Berglund UW, Soderberg-Naucler C, Stenmark P, Helleday T Cell Chem Biol. 2021 Jun 22. pii: S2451-9456(21)00268-3. doi:, 10.1016/j.chembiol.2021.06.001. PMID:34192523<ref>PMID:34192523</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7aom" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Nudix hydrolase 3D structures|Nudix hydrolase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Helleday T]] | [[Category: Helleday T]] | ||
Latest revision as of 15:13, 1 February 2024
Structure of NUDT15 in complex with Ganciclovir triphosphateStructure of NUDT15 in complex with Ganciclovir triphosphate
Structural highlights
FunctionNUD15_HUMAN Mediates the hydrolysis of some nucleoside diphosphate derivatives. Can degrade 8-oxo-dGTP in vitro, suggesting that it may remove an oxidatively damaged form of guanine (7,8-dihydro-8-oxoguanine) from DNA and the nucleotide pool, thereby preventing misincorporation of 8-oxo-dGTP into DNA thus preventing A:T to C:G transversions. Its substrate specificity in vivo however remains unclear (By similarity). May have a role in DNA synthesis and cell cycle progression through the interaction with PCNA.[1] [2] Publication Abstract from PubMedGanciclovir (GCV) is the first-line therapy against human cytomegalovirus (HCMV), a widespread infection that is particularly dangerous for immunodeficient individuals. Closely resembling deoxyguanosine triphosphate, the tri-phosphorylated metabolite of GCV (GCV-TP) is preferentially incorporated by the viral DNA polymerase, thereby terminating chain extension and, eventually, viral replication. However, the treatment outcome of GCV varies greatly among individuals, therefore warranting better understanding of its metabolism. Here we show that NUDT15, a Nudix hydrolase known to metabolize thiopurine triphosphates, can similarly hydrolyze GCV-TP through biochemical studies and co-crystallization of the NUDT15/GCV-TP complex. More critically, GCV efficacy was potentiated in HCMV-infected cells following NUDT15 depletion by RNAi or inhibition by an in-house-developed, nanomolar NUDT15 inhibitor, TH8321, suggesting that pharmacological targeting of NUDT15 is a possible avenue to improve existing anti-HCMV regimens. Collectively, the data further implicate NUDT15 as a broad-spectrum metabolic regulator of nucleoside analog therapeutics, such as thiopurines and GCV. NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir.,Zhang SM, Rehling D, Jemth AS, Throup A, Landazuri N, Almlof I, Gottmann M, Valerie NCK, Borhade SR, Wakchaure P, Page BDG, Desroses M, Homan EJ, Scobie M, Rudd SG, Berglund UW, Soderberg-Naucler C, Stenmark P, Helleday T Cell Chem Biol. 2021 Jun 22. pii: S2451-9456(21)00268-3. doi:, 10.1016/j.chembiol.2021.06.001. PMID:34192523[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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