View source for 6ehh


==Crystal structure of mouse MTH1 mutant L116M with inhibitor TH588==
<StructureSection load='6ehh' size='340' side='right' caption='[[6ehh]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ehh]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EHH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EHH FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2GE:N~4~-CYCLOPROPYL-6-(2,3-DICHLOROPHENYL)PYRIMIDINE-2,4-DIAMINE'>2GE</scene>, <scene name='pdbligand=CU:COPPER+(II)+ION'>CU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5mze|5mze]], [[5mzf|5mzf]], [[5mzg|5mzg]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Nudt1, Mth1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=6ehh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ehh OCA], [http://pdbe.org/6ehh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ehh RCSB], [http://www.ebi.ac.uk/pdbsum/6ehh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ehh ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/8ODP_MOUSE 8ODP_MOUSE]] 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. Does not play a role in U8 snoRNA decapping activity. Binds U8 snoRNA.<ref>PMID:7592783</ref>  
<div style="background-color:#fffaf0;">
== 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<ref>PMID:29281266</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ehh" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Lk3 transgenic mice]]
[[Category: Almlof, I]]
[[Category: Berglund, U Warpman]]
[[Category: Gustafsson, R]]
[[Category: Helleday, T]]
[[Category: Jemth, A S]]
[[Category: Narwal, M]]
[[Category: Stenmark, P]]
[[Category: Hydrolase]]
[[Category: Inhibitor]]
[[Category: Mouse]]
[[Category: Mth1]]
[[Category: Mutant]]