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| | <StructureSection load='5lpg' size='340' side='right'caption='[[5lpg]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='5lpg' size='340' side='right'caption='[[5lpg]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5lpg]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LPG OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5LPG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5lpg]] 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=5LPG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LPG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=71V:[(2~{R},3~{S},4~{R},5~{R})-5-(2-AZANYL-6-SULFANYL-PURIN-9-YL)-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHYL+DIHYDROGEN+PHOSPHATE'>71V</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.7Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NUDT15, MTH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=71V:[(2~{R},3~{S},4~{R},5~{R})-5-(2-AZANYL-6-SULFANYL-PURIN-9-YL)-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHYL+DIHYDROGEN+PHOSPHATE'>71V</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/8-oxo-dGTP_diphosphatase 8-oxo-dGTP diphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.55 3.6.1.55] </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=5lpg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lpg OCA], [https://pdbe.org/5lpg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lpg RCSB], [https://www.ebi.ac.uk/pdbsum/5lpg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lpg ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5lpg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lpg OCA], [http://pdbe.org/5lpg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lpg RCSB], [http://www.ebi.ac.uk/pdbsum/5lpg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lpg ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 8-oxo-dGTP diphosphatase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bevc, L]] | + | [[Category: Bevc L]] |
| - | [[Category: Carter, M]] | + | [[Category: Carter M]] |
| - | [[Category: Hagenkort, A]] | + | [[Category: Hagenkort A]] |
| - | [[Category: Helleday, T]] | + | [[Category: Helleday T]] |
| - | [[Category: Herr, P]] | + | [[Category: Herr P]] |
| - | [[Category: Homan, E]] | + | [[Category: Homan E]] |
| - | [[Category: Jemth, A S]] | + | [[Category: Jemth A-S]] |
| - | [[Category: Masuyer, G]] | + | [[Category: Masuyer G]] |
| - | [[Category: Page, B D.G]] | + | [[Category: Page BDG]] |
| - | [[Category: Rehling, D]] | + | [[Category: Rehling D]] |
| - | [[Category: Stenmark, P]] | + | [[Category: Stenmark P]] |
| - | [[Category: Valerie, N C.K]] | + | [[Category: Valerie NCK]] |
| - | [[Category: Cancer]]
| + | |
| - | [[Category: Dna repair enzyme]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Mth2]]
| + | |
| Structural highlights
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
Thiopurines are a standard treatment for childhood leukemia, but like all chemotherapeutics their use is limited by inherent or acquired resistance in patients. Recently, the nucleoside diphosphate hydrolase NUDT15 has received attention based on its ability to hydrolyze the thiopurine effector metabolites 6-thio-deoxy-GTP (dGTP) and 6-thio-GTP, thereby limiting the efficacy of thiopurines. In particular, increasing evidence suggests an association between the NUDT15 missense variant, R139C and thiopurine sensitivity. In this study, we elucidated the role of NUDT15 and NUDT15 R139C in thiopurine metabolism. In vitro and cellular results argued that 6-thio-dGTP and 6-thio-GTP are favored substrates for NUDT15, a finding supported by a crystallographic determination of NUDT15 in complex with 6-thio-GMP. We found that NUDT15 R139C mutation did not affect enzymatic activity but instead negatively influenced protein stability, likely due to a loss of supportive intramolecular bonds that caused rapid proteasomal degradation in cells. Mechanistic investigations in cells indicated that NUDT15 ablation potentiated induction of the DNA damage checkpoint and cancer cell death by 6-thioguanine. Taken together, our results defined how NUDT15 limits thiopurine efficacy and how genetic ablation via the R139C missense mutation confers sensitivity to thiopurine treatment in patients.
NUDT15 hydrolyzes 6-thio-deoxyGTP to mediate the anticancer efficacy of 6-thioguanine.,Valerie NC, Hagenkort A, Page BD, Masuyer G, Rehling D, Carter M, Bevc L, Herr P, Homan E, Sheppard NG, Stenmark P, Jemth AS, Helleday T Cancer Res. 2016 Aug 16. pii: canres.0584.2016. PMID:27530327[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
- ↑ Valerie NC, Hagenkort A, Page BD, Masuyer G, Rehling D, Carter M, Bevc L, Herr P, Homan E, Sheppard NG, Stenmark P, Jemth AS, Helleday T. NUDT15 hydrolyzes 6-thio-deoxyGTP to mediate the anticancer efficacy of 6-thioguanine. Cancer Res. 2016 Aug 16. pii: canres.0584.2016. PMID:27530327 doi:http://dx.doi.org/10.1158/0008-5472.CAN-16-0584
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