4n1u

From Proteopedia

(Difference between revisions)

Current revision

Structure of human MTH1 in complex with TH588

Structural highlights

4n1u 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 1.6Å
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

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.,Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Strom CE, Svensson LM, Schultz N, Lundback T, Einarsdottir BO, Saleh A, Gokturk C, Baranczewski P, Svensson R, Berntsson RP, Gustafsson R, Stromberg K, Sanjiv K, Jacques-Cordonnier MC, Desroses M, Gustavsson AL, Olofsson R, Johansson F, Homan EJ, Loseva O, Brautigam L, Johansson L, Hoglund A, Hagenkort A, Pham T, Altun M, Gaugaz FZ, Vikingsson S, Evers B, Henriksson M, Vallin KS, Wallner OA, Hammarstrom LG, Wiita E, Almlof I, Kalderen C, Axelsson H, Djureinovic T, Puigvert JC, Haggblad M, Jeppsson F, Martens U, Lundin C, Lundgren B, Granelli I, Jensen AJ, Artursson P, Nilsson JA, Stenmark P, Scobie M, Berglund UW, Helleday T Nature. 2014 Apr 10;508(7495):215-21. doi: 10.1038/nature13181. Epub 2014 Apr 2. PMID:24695224^[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
↑ Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Strom CE, Svensson LM, Schultz N, Lundback T, Einarsdottir BO, Saleh A, Gokturk C, Baranczewski P, Svensson R, Berntsson RP, Gustafsson R, Stromberg K, Sanjiv K, Jacques-Cordonnier MC, Desroses M, Gustavsson AL, Olofsson R, Johansson F, Homan EJ, Loseva O, Brautigam L, Johansson L, Hoglund A, Hagenkort A, Pham T, Altun M, Gaugaz FZ, Vikingsson S, Evers B, Henriksson M, Vallin KS, Wallner OA, Hammarstrom LG, Wiita E, Almlof I, Kalderen C, Axelsson H, Djureinovic T, Puigvert JC, Haggblad M, Jeppsson F, Martens U, Lundin C, Lundgren B, Granelli I, Jensen AJ, Artursson P, Nilsson JA, Stenmark P, Scobie M, Berglund UW, Helleday T. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature. 2014 Apr 10;508(7495):215-21. doi: 10.1038/nature13181. Epub 2014 Apr 2. PMID:24695224 doi:http://dx.doi.org/10.1038/nature13181

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/4n1u"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4n1u]] 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=4N1U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N1U FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2GE:N~4~-CYCLOPROPYL-6-(2,3-DICHLOROPHENYL)PYRIMIDINE-2,4-DIAMINE'>2GE</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]] 1.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2GE:N~4~-CYCLOPROPYL-6-(2,3-DICHLOROPHENYL)PYRIMIDINE-2,4-DIAMINE'>2GE</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'>[https://proteopedia.org/fgij/fg.htm?mol=4n1u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n1u OCA], [https://pdbe.org/4n1u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n1u RCSB], [https://www.ebi.ac.uk/pdbsum/4n1u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n1u ProSAT]</span></td></tr>
 </table>

4n1u

From Proteopedia

Current revision

Structure of human MTH1 in complex with TH588

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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