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| | ==Crystal structure of MTH1 in complex with 3-isomangostin== | | ==Crystal structure of MTH1 in complex with 3-isomangostin== |
| - | <StructureSection load='6aa5' size='340' side='right' caption='[[6aa5]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='6aa5' size='340' side='right'caption='[[6aa5]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6aa5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AA5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AA5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6aa5]] is a 1 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=6AA5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AA5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MKU:5,9-DIHYDROXY-8-METHOXY-2,2-DIMETHYL-7-(3-METHYLBUT-2-EN-1-YL)-3,4-DIHYDRO-2H,6H-PYRANO[3,2-B]XANTHEN-6-ONE'>MKU</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.901Å</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=6aa5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6aa5 OCA], [http://pdbe.org/6aa5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6aa5 RCSB], [http://www.ebi.ac.uk/pdbsum/6aa5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6aa5 ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MKU:5,9-DIHYDROXY-8-METHOXY-2,2-DIMETHYL-7-(3-METHYLBUT-2-EN-1-YL)-3,4-DIHYDRO-2H,6H-PYRANO[3,2-B]XANTHEN-6-ONE'>MKU</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=6aa5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6aa5 OCA], [https://pdbe.org/6aa5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6aa5 RCSB], [https://www.ebi.ac.uk/pdbsum/6aa5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6aa5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/8ODP_HUMAN 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.<ref>PMID:10373420</ref> <ref>PMID:10608900</ref> <ref>PMID:11139615</ref> <ref>PMID:12857738</ref> <ref>PMID:22556419</ref> | + | [https://www.uniprot.org/uniprot/8ODP_HUMAN 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.<ref>PMID:10373420</ref> <ref>PMID:10608900</ref> <ref>PMID:11139615</ref> <ref>PMID:12857738</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: Kitakami, R]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Mizuguchi, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Yokoyama, T]] | + | [[Category: Kitakami R]] |
| - | [[Category: Antitumor protein]] | + | [[Category: Mizuguchi M]] |
| - | [[Category: Hydrolase]] | + | [[Category: Yokoyama T]] |
| - | [[Category: Nudt1]]
| + | |
| Structural highlights
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
MutT homologue 1 (MTH1) protects the nucleotide pool from oxidative stress by hydrolyzing oxidized nucleoside triphosphates and prevents their incorporation into DNA. Cancer cells are dependent on the MTH1 activity for survival due to the high-level of reactive oxygen species in cancer cells; therefore, MTH1 is considered to be a novel target for treatment of various cancers. Here, we show by X-ray crystallographic screening using an in-house cocktail library that alpha-mangostin, a natural xanthone from mangosteen pericarp, binds to the active site of MTH1. A subsequent inhibition assay revealed that 3-isomangostin, a cyclized derivative of alpha-mangostin, was the most potent MTH1 inhibitor, with an IC50 value of 0.052muM. Detailed structural analyses of the MTH1-3-isomangostin complex showed the novel binding mode of 3-isomangostin. Our results demonstrate that X-ray crystallographic screening is useful for the lead discovery for MTH1, and suggest that 3-isomangostin would be an attractive chemical tool for the development of anticancer agents.
Discovery of a new class of MTH1 inhibitor by X-ray crystallographic screening.,Yokoyama T, Kitakami R, Mizuguchi M Eur J Med Chem. 2019 Apr 1;167:153-160. doi: 10.1016/j.ejmech.2019.02.011. Epub, 2019 Feb 7. PMID:30771603[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
- ↑ Yokoyama T, Kitakami R, Mizuguchi M. Discovery of a new class of MTH1 inhibitor by X-ray crystallographic screening. Eur J Med Chem. 2019 Apr 1;167:153-160. doi: 10.1016/j.ejmech.2019.02.011. Epub, 2019 Feb 7. PMID:30771603 doi:http://dx.doi.org/10.1016/j.ejmech.2019.02.011
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