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6us2
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 6us2 is ON HOLD Authors: Newby, Z.E.R., Lansdon, E.B. Description: MTH1 in complex with compound 5 Category: Unreleased Structures [[Category: ...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==MTH1 in complex with compound 5== | |
| + | <StructureSection load='6us2' size='340' side='right'caption='[[6us2]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6us2]] 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=6US2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6US2 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]] 1.8001266Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S3O:N-[5-(2,3-dimethylphenyl)-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl]acetamide'>S3O</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=6us2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6us2 OCA], [https://pdbe.org/6us2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6us2 RCSB], [https://www.ebi.ac.uk/pdbsum/6us2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6us2 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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 6us2" style="background-color:#fffaf0;"></div> |
| - | [[Category: Lansdon | + | |
| + | ==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]] | ||
Current revision
MTH1 in complex with compound 5
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