|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==MTH1 substrate recognition: Complex with a methylbenzimidazolyl acetamide.== | | ==MTH1 substrate recognition: Complex with a methylbenzimidazolyl acetamide.== |
| - | <StructureSection load='5fsm' size='340' side='right' caption='[[5fsm]], [[Resolution|resolution]] 1.67Å' scene=''> | + | <StructureSection load='5fsm' size='340' side='right'caption='[[5fsm]], [[Resolution|resolution]] 1.67Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5fsm]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FSM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FSM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5fsm]] 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=5FSM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FSM 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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=N91:N-(1-METHYLBENZIMIDAZOL-5-YL)ACETAMIDE'>N91</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]] 1.67Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5fsi|5fsi]], [[5fsk|5fsk]], [[5fsl|5fsl]], [[5fsn|5fsn]], [[5fso|5fso]]</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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=N91:N-(1-METHYLBENZIMIDAZOL-5-YL)ACETAMIDE'>N91</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=5fsm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fsm OCA], [http://pdbe.org/5fsm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fsm RCSB], [http://www.ebi.ac.uk/pdbsum/5fsm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fsm 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=5fsm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fsm OCA], [https://pdbe.org/5fsm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fsm RCSB], [https://www.ebi.ac.uk/pdbsum/5fsm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fsm 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 == |
| Line 21: |
Line 21: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[7%2C8-dihydro-8-oxoguanine triphosphatase|7%2C8-dihydro-8-oxoguanine triphosphatase]] | + | *[[7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures|7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bista, M]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Breed, J]] | + | [[Category: Large Structures]] |
| - | [[Category: Carter, N]] | + | [[Category: Bista M]] |
| - | [[Category: Embrey, K]] | + | [[Category: Breed J]] |
| - | [[Category: Nissink, J W.M]] | + | [[Category: Carter N]] |
| - | [[Category: Phillips, C]] | + | [[Category: Embrey K]] |
| - | [[Category: Read, J]] | + | [[Category: Nissink JWM]] |
| - | [[Category: Winter, J J]] | + | [[Category: Phillips C]] |
| - | [[Category: Hydrolase]]
| + | [[Category: Read J]] |
| - | [[Category: Nudt1]]
| + | [[Category: Winter JJ]] |
| 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
MTH1 (NUDT1) is an oncologic target involved in the prevention of DNA damage. We investigate the way MTH1 recognises its substrates and present substrate-bound structures of MTH1 for 8-oxo-dGTP and 8-oxo-rATP as examples of novel strong and weak binding substrate motifs. Investigation of a small set of purine-like fragments using 2D NMR resulted in identification of a fragment with weak potency. The protein-ligand X-Ray structure of this fragment provides insight into the role of water molecules in substrate selectivity. Wider fragment screening by NMR resulted in three new protein structures exhibiting alternative binding configurations to the key Asp-Asp recognition element of the protein. These inhibitor binding modes demonstrate that MTH1 employs an intricate yet promiscuous mechanism of substrate anchoring through its Asp-Asp pharmacophore. The structures suggest that water-mediated interactions convey selectivity towards oxidized substrates over their non-oxidised counterparts, in particular by stabilization of a water molecule in a hydrophobic environment through hydrogen bonding. These findings may be useful in the design of inhibitors of MTH1.
MTH1 Substrate Recognition--An Example of Specific Promiscuity.,Nissink JW, Bista M, Breed J, Carter N, Embrey K, Read J, Winter-Holt JJ PLoS One. 2016 Mar 21;11(3):e0151154. doi: 10.1371/journal.pone.0151154., eCollection 2016. PMID:26999531[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Nissink JW, Bista M, Breed J, Carter N, Embrey K, Read J, Winter-Holt JJ. MTH1 Substrate Recognition--An Example of Specific Promiscuity. PLoS One. 2016 Mar 21;11(3):e0151154. doi: 10.1371/journal.pone.0151154., eCollection 2016. PMID:26999531 doi:http://dx.doi.org/10.1371/journal.pone.0151154
|
