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5mzf

From Proteopedia

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Crystal structure of dog MTH1 protein

Structural highlights

5mzf is a 4 chain structure with sequence from Canis lupus familiaris. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

8ODP_CANLF Oxidized purine nucleoside triphosphate hydrolase which is a prominent sanitizer of the oxidized nucleotide pool (PubMed:30304478, PubMed:32144205, PubMed:29281266). Catalyzes the hydrolysis of 2-oxo-dATP (2-hydroxy-dATP) into 2-oxo-dAMP (By similarity). Has also a significant hydrolase activity toward 2-oxo-ATP, 8-oxo-dGTP and 8-oxo-dATP (PubMed:30304478, PubMed:32144205, PubMed:29281266). Through the hydrolysis of oxidized purine nucleoside triphosphates, prevents their incorporation into DNA and the subsequent transversions A:T to C:G and G:C to T:A (PubMed:30304478, PubMed:32144205, PubMed:29281266). Also catalyzes the hydrolysis of methylated purine nucleoside triphosphate preventing their integration into DNA (PubMed:30304478, PubMed:32144205). Through this antimutagenic activity protects cells from oxidative stress (PubMed:30304478, PubMed:32144205, PubMed:29281266).[UniProtKB:P36639]^[1] ^[2] ^[3]

Publication Abstract from PubMed

MTH1 hydrolyzes oxidized nucleoside triphosphates, thereby sanitizing the nucleotide pool from oxidative damage. This prevents incorporation of damaged nucleotides into DNA, which otherwise would lead to mutations and cell death. The high level of reactive oxygen species in cancer cells leads to a higher level of oxidized nucleotides in cancer cells compared to non-malignant cells making cancer cells more dependent on MTH1 for survival. The possibility to specifically target cancer cells by inhibiting MTH1 has highlighted MTH1 as a promising cancer target. Progression of MTH1 inhibitors into the clinic requires animal studies and knowledge about species differences in potency of inhibitors are of vital importance. We here show that the human MTH1 inhibitor TH588 is approximately twenty fold less potent for inhibition of mouse MTH1 compared to human, rat, pig, and dog MTH1. We present the crystal structures of mouse MTH1 in complex with TH588 and dog MTH1and elucidate the structural and sequence basis for the observed difference in affinity for TH588. We identify amino acid residue 116 in MTH1 as an important determinant for TH588 affinity. Furthermore, we present the structure of mouse MTH1 in complex with the substrate 8-oxo-dGTP. The crystal structures provide insight into the high degree of structural conservation between MTH1 from different organisms and provide a detailed view of interactions between MTH1 and the inhibitor, revealing that minute structural differences can have a large impact on affinity and specificity.

Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity.,Narwal M, Jemth AS, Gustafsson R, Almlof I, Warpman Berglund U, Helleday T, Stenmark P Biochemistry. 2017 Dec 27. doi: 10.1021/acs.biochem.7b01163. PMID:29281266^[4]

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

References

↑ Narwal M, Jemth AS, Gustafsson R, Almlof I, Warpman Berglund U, Helleday T, Stenmark P. Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity. Biochemistry. 2017 Dec 27. doi: 10.1021/acs.biochem.7b01163. PMID:29281266 doi:http://dx.doi.org/10.1021/acs.biochem.7b01163
↑ Jemth AS, Gustafsson R, Brautigam L, Henriksson L, Vallin KSA, Sarno A, Almlof I, Homan E, Rasti A, Warpman Berglund U, Stenmark P, Helleday T. MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP. Nucleic Acids Res. 2018 Oct 10. pii: 5124590. doi: 10.1093/nar/gky896. PMID:30304478 doi:http://dx.doi.org/10.1093/nar/gky896
↑ Scaletti ER, Vallin KS, Brautigam L, Sarno A, Warpman Berglund U, Helleday T, Stenmark P, Jemth AS. MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool. J Biol Chem. 2020 Apr 10;295(15):4761-4772. doi: 10.1074/jbc.RA120.012636. Epub, 2020 Mar 6. PMID:32144205 doi:http://dx.doi.org/10.1074/jbc.RA120.012636
↑ Narwal M, Jemth AS, Gustafsson R, Almlof I, Warpman Berglund U, Helleday T, Stenmark P. Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity. Biochemistry. 2017 Dec 27. doi: 10.1021/acs.biochem.7b01163. PMID:29281266 doi:http://dx.doi.org/10.1021/acs.biochem.7b01163

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5mzf"

@@ Line 1: / Line 1: @@
 ==Crystal structure of dog MTH1 protein==
-<StructureSection load='5mzf' size='340' side='right' caption='[[5mzf]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='5mzf' size='340' side='right'caption='[[5mzf]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5mzf]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Canlf Canlf]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MZF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MZF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5mzf]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Canis_lupus_familiaris Canis lupus familiaris]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MZF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MZF FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NUDT1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9615 CANLF])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5mzf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mzf OCA], [http://pdbe.org/5mzf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mzf RCSB], [http://www.ebi.ac.uk/pdbsum/5mzf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mzf ProSAT]</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=5mzf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mzf OCA], [https://pdbe.org/5mzf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mzf RCSB], [https://www.ebi.ac.uk/pdbsum/5mzf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mzf ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/8ODP_CANLF 8ODP_CANLF] Oxidized purine nucleoside triphosphate hydrolase which is a prominent sanitizer of the oxidized nucleotide pool (PubMed:30304478, PubMed:32144205, PubMed:29281266). Catalyzes the hydrolysis of 2-oxo-dATP (2-hydroxy-dATP) into 2-oxo-dAMP (By similarity). Has also a significant hydrolase activity toward 2-oxo-ATP, 8-oxo-dGTP and 8-oxo-dATP (PubMed:30304478, PubMed:32144205, PubMed:29281266). Through the hydrolysis of oxidized purine nucleoside triphosphates, prevents their incorporation into DNA and the subsequent transversions A:T to C:G and G:C to T:A (PubMed:30304478, PubMed:32144205, PubMed:29281266). Also catalyzes the hydrolysis of methylated purine nucleoside triphosphate preventing their integration into DNA (PubMed:30304478, PubMed:32144205). Through this antimutagenic activity protects cells from oxidative stress (PubMed:30304478, PubMed:32144205, PubMed:29281266).[UniProtKB:P36639]<ref>PMID:29281266</ref> <ref>PMID:30304478</ref> <ref>PMID:32144205</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 17: / Line 19: @@
 </div>
 <div class="pdbe-citations 5mzf" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures|7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Canlf]]
+[[Category: Canis lupus familiaris]]
-[[Category: Helleday, T]]
+[[Category: Large Structures]]
-[[Category: Jemth, A S]]
+[[Category: Helleday T]]
-[[Category: Narwal, M]]
+[[Category: Jemth A-S]]
-[[Category: Stenmark, P]]
+[[Category: Narwal M]]
-[[Category: Drug target]]
+[[Category: Stenmark P]]
-[[Category: Hydrolase]]

5mzf

From Proteopedia

Current revision

Crystal structure of dog MTH1 protein

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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