7aom

From Proteopedia

(Difference between revisions)

Revision as of 10:05, 21 December 2022

Structure of NUDT15 in complex with Ganciclovir triphosphate

Structural highlights

7aom is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2]

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^[3]

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

References

↑ Yu Y, Cai JP, Tu B, Wu L, Zhao Y, Liu X, Li L, McNutt MA, Feng J, He Q, Yang Y, Wang H, Sekiguchi M, Zhu WG. Proliferating cell nuclear antigen is protected from degradation by forming a complex with MutT Homolog2. J Biol Chem. 2009 Jul 17;284(29):19310-20. doi: 10.1074/jbc.M109.015289. Epub, 2009 May 6. PMID:19419956 doi:http://dx.doi.org/10.1074/jbc.M109.015289
↑ Takagi Y, Setoyama D, Ito R, Kamiya H, Yamagata Y, Sekiguchi M. Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2. J Biol Chem. 2012 Jun 15;287(25):21541-9. doi: 10.1074/jbc.M112.363010. Epub 2012, May 3. PMID:22556419 doi:10.1074/jbc.M112.363010
↑ 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. NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir. Cell Chem Biol. 2021 Jun 22. pii: S2451-9456(21)00268-3. doi:, 10.1016/j.chembiol.2021.06.001. PMID:34192523 doi:http://dx.doi.org/10.1016/j.chembiol.2021.06.001

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/7aom"

@@ Line 3: / Line 3: @@
 <StructureSection load='7aom' size='340' side='right'caption='[[7aom]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7aom]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. 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='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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NUDT15, MTH2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Nucleotide_diphosphatase Nucleotide diphosphatase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.9 3.6.1.9] </span></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>
 == 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>
+[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 ==
@@ Line 24: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Nucleotide diphosphatase]]
+[[Category: Helleday T]]
-[[Category: Helleday, T]]
+[[Category: Rehling D]]
-[[Category: Rehling, D]]
+[[Category: Stenmark P]]
-[[Category: Stenmark, P]]
+[[Category: Zhang SM]]
-[[Category: Zhang, S M]]
-[[Category: Antiviral]]
-[[Category: Hydrolase]]
-[[Category: Nudix hydrolase]]

7aom

From Proteopedia

Revision as of 10:05, 21 December 2022

Structure of NUDT15 in complex with Ganciclovir triphosphate

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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