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8i1j

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Current revision

Crystal structure of human MTH1(G2K/D120N mutant) in complex with 2-oxo-dATP at pH 9.7

Structural highlights

8i1j 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.
Method:	X-ray diffraction, Resolution 1.08Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

8ODP_HUMAN Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Human MutT homolog 1 (MTH1), also known as Nudix type motif 1 (NUDT1), hydrolyzes 8-oxo-dGTP and 2-oxo-dATP with broad substrate recognition and has attracted attention in anti-cancer therapeutics. Previous studies on MTH1 have proposed that the exchange of the protonation state between Asp119 and Asp120 is essential for the broad substrate recognition of MTH1. To understand the relationship between protonation states and substrate binding, we determined the crystal structures of MTH1 at pH 7.7-9.7. With increasing pH, MTH1 gradually loses its substrate-binding ability, indicating that Asp119 is deprotonated at pH 8.0-9.1 in 8-oxo-dGTP recognition and Asp120 is deprotonated at pH 8.6-9.7 in 2-oxo-dATP recognition. These results confirm that MTH1 recognizes 8-oxo-dGTP and 2-oxo-dATP by exchanging the protonation state between Asp119 and Asp120 with higher pK(a) .

Protonation states of Asp residues in the human Nudix hydrolase MTH1 contribute to its broad substrate recognition.,Nakamura T, Koga-Ogawa Y, Fujimiya K, Chirifu M, Goto M, Ikemizu S, Nakabeppu Y, Yamagata Y FEBS Lett. 2023 Mar 13. doi: 10.1002/1873-3468.14611. PMID:36914375^[6]

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

References

↑ Fujikawa K, Kamiya H, Yakushiji H, Fujii Y, Nakabeppu Y, Kasai H. The oxidized forms of dATP are substrates for the human MutT homologue, the hMTH1 protein. J Biol Chem. 1999 Jun 25;274(26):18201-5. PMID:10373420
↑ Fujii Y, Shimokawa H, Sekiguchi M, Nakabeppu Y. Functional significance of the conserved residues for the 23-residue module among MTH1 and MutT family proteins. J Biol Chem. 1999 Dec 31;274(53):38251-9. PMID:10608900
↑ Fujikawa K, Kamiya H, Yakushiji H, Nakabeppu Y, Kasai H. Human MTH1 protein hydrolyzes the oxidized ribonucleotide, 2-hydroxy-ATP. Nucleic Acids Res. 2001 Jan 15;29(2):449-54. PMID:11139615
↑ Yoshimura D, Sakumi K, Ohno M, Sakai Y, Furuichi M, Iwai S, Nakabeppu Y. An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. J Biol Chem. 2003 Sep 26;278(39):37965-73. Epub 2003 Jul 10. PMID:12857738 doi:10.1074/jbc.M306201200
↑ 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
↑ Nakamura T, Koga-Ogawa Y, Fujimiya K, Chirifu M, Goto M, Ikemizu S, Nakabeppu Y, Yamagata Y. Protonation states of Asp residues in the human Nudix hydrolase MTH1 contribute to its broad substrate recognition. FEBS Lett. 2023 Mar 13. PMID:36914375 doi:10.1002/1873-3468.14611

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/8i1j"

Categories: Homo sapiens | Large Structures | Nakamura T | Yamagata Y

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8i1j]] 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=8I1J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8I1J FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6U4:[[(2R,3S,5R)-5-(6-AZANYL-2-OXIDANYLIDENE-1H-PURIN-9-YL)-3-OXIDANYL-OXOLAN-2-YL]METHOXY-OXIDANYL-PHOSPHORYL]+PHOSPHONO+HYDROGEN+PHOSPHATE'>6U4</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 1.08&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6U4:[[(2R,3S,5R)-5-(6-AZANYL-2-OXIDANYLIDENE-1H-PURIN-9-YL)-3-OXIDANYL-OXOLAN-2-YL]METHOXY-OXIDANYL-PHOSPHORYL]+PHOSPHONO+HYDROGEN+PHOSPHATE'>6U4</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=8i1j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8i1j OCA], [https://pdbe.org/8i1j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8i1j RCSB], [https://www.ebi.ac.uk/pdbsum/8i1j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8i1j ProSAT]</span></td></tr>
 </table>

8i1j

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Current revision

Crystal structure of human MTH1(G2K/D120N mutant) in complex with 2-oxo-dATP at pH 9.7

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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