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6us2
From Proteopedia
(Difference between revisions)
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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. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6US2 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6us2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6us2 OCA], [http://pdbe.org/6us2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6us2 RCSB], [http://www.ebi.ac.uk/pdbsum/6us2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6us2 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> | ||
| + | <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: Newby, Z | + | <div class="pdbe-citations 6us2" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Lansdon, E B]] | ||
| + | [[Category: Newby, Z E.R]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Nudix hydrolase]] | ||
| + | [[Category: Nudt1]] | ||
Revision as of 09:22, 1 April 2020
MTH1 in complex with compound 5
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