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5nhy

From Proteopedia

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Current revision

BAY-707 in complex with MTH1

Structural highlights

5nhy 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 1.72Å
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

MTH1 is a hydrolase responsible for sanitization of oxidized purine nucleoside triphosphates to prevent their incorporation into replicating DNA. Early tool compounds published in the literature inhibited the enzymatic activity of MTH1 and subsequently induced cancer cell death; however recent studies have questioned the reported link between these two events. Therefore, it is important to validate MTH1 as a cancer dependency with high quality chemical probes. Here, we present BAY-707, a substrate-competitive, highly potent and selective inhibitor of MTH1, chemically distinct compared to those previously published. Despite superior cellular target engagement and pharmacokinetic properties, inhibition of MTH1 with BAY-707 resulted in a clear lack of in vitro or in vivo anticancer efficacy either in mono- or in combination therapies. Therefore, we conclude that MTH1 is dispensable for cancer cell survival.

Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target.,Ellermann M, Eheim A, Rahm F, Viklund J, Guenther J, Andersson M, Ericsson U, Forsblom R, Ginman T, Lindstrom J, Silvander C, Tresaugues L, Giese A, Bunse S, Neuhaus R, Weiske J, Quanz M, Glasauer A, Nowak-Reppel K, Bader B, Irlbacher H, Meyer H, Queisser N, Bauser M, Haegebarth A, Gorjanacz M ACS Chem Biol. 2017 Aug 18;12(8):1986-1992. doi: 10.1021/acschembio.7b00370. Epub, 2017 Jul 12. PMID:28679043^[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
↑ Ellermann M, Eheim A, Rahm F, Viklund J, Guenther J, Andersson M, Ericsson U, Forsblom R, Ginman T, Lindstrom J, Silvander C, Tresaugues L, Giese A, Bunse S, Neuhaus R, Weiske J, Quanz M, Glasauer A, Nowak-Reppel K, Bader B, Irlbacher H, Meyer H, Queisser N, Bauser M, Haegebarth A, Gorjanacz M. Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target. ACS Chem Biol. 2017 Aug 18;12(8):1986-1992. doi: 10.1021/acschembio.7b00370. Epub, 2017 Jul 12. PMID:28679043 doi:http://dx.doi.org/10.1021/acschembio.7b00370

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/5nhy"

@@ Line 3: / Line 3: @@
 <StructureSection load='5nhy' size='340' side='right'caption='[[5nhy]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5nhy]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NHY OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5NHY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5nhy]] 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=5NHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NHY FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8XT:~{N}-ethyl-4-[(3~{S})-3-methylmorpholin-4-yl]-1~{H}-pyrrolo[2,3-b]pyridine-2-carboxamide'>8XT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 1.72&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5nhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nhy OCA], [http://pdbe.org/5nhy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nhy RCSB], [http://www.ebi.ac.uk/pdbsum/5nhy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nhy ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8XT:~{N}-ethyl-4-[(3~{S})-3-methylmorpholin-4-yl]-1~{H}-pyrrolo[2,3-b]pyridine-2-carboxamide'>8XT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=5nhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nhy OCA], [https://pdbe.org/5nhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nhy RCSB], [https://www.ebi.ac.uk/pdbsum/5nhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nhy ProSAT]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Andersson, M]]
+[[Category: Andersson M]]
-[[Category: Bader, B]]
+[[Category: Bader B]]
-[[Category: Bunse, S]]
+[[Category: Bunse S]]
-[[Category: Eheim, A]]
+[[Category: Eheim A]]
-[[Category: Ellermann, M]]
+[[Category: Ellermann M]]
-[[Category: Ericsson, U]]
+[[Category: Ericsson U]]
-[[Category: Forsblom, R]]
+[[Category: Forsblom R]]
-[[Category: Giese, A]]
+[[Category: Giese A]]
-[[Category: Ginman, T]]
+[[Category: Ginman T]]
-[[Category: Glasauer, A]]
+[[Category: Glasauer A]]
-[[Category: Gorjanacz, M]]
+[[Category: Gorjanacz M]]
-[[Category: Irlbacher, H]]
+[[Category: Irlbacher H]]
-[[Category: Lindstrom, J]]
+[[Category: Lindstrom J]]
-[[Category: Meyer, H]]
+[[Category: Meyer H]]
-[[Category: Neuhaus, R]]
+[[Category: Neuhaus R]]
-[[Category: Nowak-Reppel, K]]
+[[Category: Nowak-Reppel K]]
-[[Category: Quanz, M]]
+[[Category: Quanz M]]
-[[Category: Queisser, N]]
+[[Category: Queisser N]]
-[[Category: Rahm, F]]
+[[Category: Rahm F]]
-[[Category: Silvander, C]]
+[[Category: Silvander C]]
-[[Category: Tresaugues, L]]
+[[Category: Tresaugues L]]
-[[Category: Viklund, J]]
+[[Category: Viklund J]]
-[[Category: Weiske, J]]
+[[Category: Weiske J]]
-[[Category: Hydrolase]]
-[[Category: Inhibitor]]
-[[Category: Nucleotide hydrolase]]
-[[Category: Nudix]]
-[[Category: Oncology]]

5nhy

From Proteopedia

Current revision

BAY-707 in complex with MTH1

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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