5anu

From Proteopedia

(Difference between revisions)

Revision as of 15:03, 2 March 2016

MTH1 in complex with compound 15

Structural highlights

5anu is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	5anv, 5anw
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

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

Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. MTH1 is one of the "housekeeping" enzymes that are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal and chemically distinct tool compounds to those published in the literature to allow us to test the hypothesis that inhibition of MTH1 has wide applicability in the treatment of cancer. Here we present the work that led to the discovery of three structurally different series of MTH1 inhibitors with excellent potency, selectivity, and proven target engagement in cells. None of these compounds elicited the reported cellular phenotype, and additional siRNA and CRISPR experiments further support these observations. Critically, the difference between the responses of our highly selective inhibitors and published tool compounds suggests that the effect reported for the latter may be due to off-target cytotoxic effects. As a result, we conclude that the role of MTH1 in carcinogenesis and utility of its inhibition is yet to be established.

Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival.,Kettle JG, Alwan H, Bista M, Breed J, Davies NL, Eckersley K, Fillery S, Foote KM, Goodwin L, Jones DR, Kack H, Lau A, Nissink JW, Read J, Scott JS, Taylor B, Walker G, Wissler L, Wylot M J Med Chem. 2016 Feb 16. PMID:26878898^[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
↑ Kettle JG, Alwan H, Bista M, Breed J, Davies NL, Eckersley K, Fillery S, Foote KM, Goodwin L, Jones DR, Kack H, Lau A, Nissink JW, Read J, Scott JS, Taylor B, Walker G, Wissler L, Wylot M. Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival. J Med Chem. 2016 Feb 16. PMID:26878898 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01760

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5anu"

Categories: Breed, J | Read, J A | Hydrolase | Inhibitor | Nudt1

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5anu is ON HOLD  until Paper Publication
+==MTH1 in complex with compound 15==
+<StructureSection load='5anu' size='340' side='right' caption='[[5anu]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5anu]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ANU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ANU FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=58T:13-(METHYLAMINO)-23,24,25-TRIOXA-17,18,19,21-TETRAZATETRACYCLO-TRICOSA-1(3),2(10),4(11),12(14),13(18),16(19)-HEXAN-15-ONE'>58T</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5anv|5anv]], [[5anw|5anw]]</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=5anu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5anu OCA], [http://pdbe.org/5anu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5anu RCSB], [http://www.ebi.ac.uk/pdbsum/5anu PDBsum]</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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. MTH1 is one of the "housekeeping" enzymes that are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal and chemically distinct tool compounds to those published in the literature to allow us to test the hypothesis that inhibition of MTH1 has wide applicability in the treatment of cancer. Here we present the work that led to the discovery of three structurally different series of MTH1 inhibitors with excellent potency, selectivity, and proven target engagement in cells. None of these compounds elicited the reported cellular phenotype, and additional siRNA and CRISPR experiments further support these observations. Critically, the difference between the responses of our highly selective inhibitors and published tool compounds suggests that the effect reported for the latter may be due to off-target cytotoxic effects. As a result, we conclude that the role of MTH1 in carcinogenesis and utility of its inhibition is yet to be established.
-Authors: Read, J.A., Breed, J.
+Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival.,Kettle JG, Alwan H, Bista M, Breed J, Davies NL, Eckersley K, Fillery S, Foote KM, Goodwin L, Jones DR, Kack H, Lau A, Nissink JW, Read J, Scott JS, Taylor B, Walker G, Wissler L, Wylot M J Med Chem. 2016 Feb 16. PMID:26878898<ref>PMID:26878898</ref>
-Description: MTH1 in complex with compound 15
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5anu" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Breed, J]]
-[[Category: Read, J.A]]
+[[Category: Read, J A]]
+[[Category: Hydrolase]]
+[[Category: Inhibitor]]
+[[Category: Nudt1]]

5anu

From Proteopedia

Revision as of 15:03, 2 March 2016

MTH1 in complex with compound 15

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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