7b66

From Proteopedia

(Difference between revisions)

Current revision

Structure of NUDT15 R139H Mutant in complex with TH7755

Structural highlights

7b66 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.6Å
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

The enzyme NUDT15 efficiently hydrolyses the active metabolites of thiopurine drugs, which are routinely used for treating cancer and inflammatory diseases. Loss-of-function variants in NUDT15 are strongly associated with thiopurine intolerance, such as leukopenia, and pre-emptive NUDT15 genotyping has been clinically implemented to personalize thiopurine dosing. However, understanding the molecular consequences of these variants has been difficult, as no structural information was available for NUDT15 proteins encoded by clinically actionable pharmacogenetic variants due to their inherent instability. Recently, the small molecule NUDT15 inhibitor TH1760 has been shown to sensitize cells to thiopurines, through enhanced accumulation of 6-thio-guanine in DNA. Building upon this, we herein report the development of the potent and specific NUDT15 inhibitor, TH7755. TH7755 demonstrates a greatly improved cellular target engagement and 6-thioguanine potentiation compared to TH1760, while showing no cytotoxicity on its own. This potent inhibitor also stabilized NUDT15, enabling analysis by X-ray crystallography. We have determined high-resolution structures of the clinically relevant NUDT15 variants Arg139Cys, Arg139His, Val18Ile and V18_V19insGlyVal. These structures provide clear insights into the structural basis for the thiopurine intolerance phenotype observed in patients carrying these pharmacogenetic variants. These findings will aid in predicting the effects of new NUDT15 sequence variations yet to be discovered in the clinic.

Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity.,Rehling D, Zhang SM, Jemth AS, Koolmeister T, Throup A, Wallner O, Scaletti E, Moriyama T, Nishii R, Davies J, Desroses M, Rudd SG, Scobie M, Homan E, Berglund UW, Yang JJ, Helleday T, Stenmark P J Biol Chem. 2021 Mar 19:100568. doi: 10.1016/j.jbc.2021.100568. PMID:33753169^[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
↑ Rehling D, Zhang SM, Jemth AS, Koolmeister T, Throup A, Wallner O, Scaletti E, Moriyama T, Nishii R, Davies J, Desroses M, Rudd SG, Scobie M, Homan E, Berglund UW, Yang JJ, Helleday T, Stenmark P. Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity. J Biol Chem. 2021 Mar 19:100568. doi: 10.1016/j.jbc.2021.100568. PMID:33753169 doi:http://dx.doi.org/10.1016/j.jbc.2021.100568

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/7b66"

Categories: Homo sapiens | Large Structures | Rehling D | Stenmark P

@@ Line 3: / Line 3: @@
 <StructureSection load='7b66' size='340' side='right'caption='[[7b66]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7b66]] is a 4 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=7B66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B66 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7b66]] is a 4 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=7B66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B66 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SYW:(R)-6-((2-methyl-4-(1-methyl-1H-indole-5-carbonyl)piperazin-1-yl)sulfonyl)benzo[d]oxazol-2(3H)-one'>SYW</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]] 1.6&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SYW:(R)-6-((2-methyl-4-(1-methyl-1H-indole-5-carbonyl)piperazin-1-yl)sulfonyl)benzo[d]oxazol-2(3H)-one'>SYW</scene></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=7b66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b66 OCA], [https://pdbe.org/7b66 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b66 RCSB], [https://www.ebi.ac.uk/pdbsum/7b66 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b66 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 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Nucleotide diphosphatase]]
+[[Category: Rehling D]]
-[[Category: Rehling, D]]
+[[Category: Stenmark P]]
-[[Category: Stenmark, P]]
-[[Category: Complex]]
-[[Category: Hydrolase]]
-[[Category: Inhibitor]]
-[[Category: Nucleoside triphosphate pyrophosphohydrolase]]

7b66

From Proteopedia

Current revision

Structure of NUDT15 R139H Mutant in complex with TH7755

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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