View source for 6us4


==MTH1 in complex with compound 32==
<StructureSection load='6us4' size='340' side='right'caption='[[6us4]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6us4]] 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=6US4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6US4 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9503291&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GN6:5-(2,3-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine'>GN6</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=6us4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6us4 OCA], [https://pdbe.org/6us4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6us4 RCSB], [https://www.ebi.ac.uk/pdbsum/6us4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6us4 ProSAT]</span></td></tr>
</table>
== Function ==
[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 ==
We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystallization of 5 with MTH1 revealed the ligand in a Phi-cis-N-(pyridin-2-yl)acetamide conformation enabling a key intramolecular hydrogen bond and polar interactions with residues Gly34 and Asp120. Modification of literature compound TH287 with O- and N-linked aryl and alkyl aryl substituents led to the discovery of potent pyrimidine-2,4,6-triamine 25 (IC50 = 0.49 nM). Triazolopyridine 32 emerged as a highly selective lead compound with a suitable in vitro profile and desirable pharmacokinetic properties in rat. Elucidation of the DNA damage response, cell viability, and intracellular concentrations of oxo-NTPs (oxidized nucleoside triphosphates) as a function of MTH1 knockdown and/or small molecule inhibition was studied. Based on our findings, we were unable to provide evidence to further pursue MTH1 as an oncology target.

Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation.,Farand J, Kropf JE, Blomgren P, Xu J, Schmitt AC, Newby ZE, Wang T, Murakami E, Barauskas O, Sudhamsu J, Feng JY, Niedziela-Majka A, Schultz BE, Schwartz K, Viatchenko-Karpinski S, Kornyeyev D, Kashishian A, Fan P, Chen X, Lansdon EB, Ports MO, Currie KS, Watkins WJ, Notte GT ACS Med Chem Lett. 2019 Nov 19;11(3):358-364. doi:, 10.1021/acsmedchemlett.9b00420. eCollection 2020 Mar 12. PMID:32184970<ref>PMID:32184970</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6us4" style="background-color:#fffaf0;"></div>

==See Also==
*[[7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures|7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lansdon EB]]
[[Category: Newby ZER]]