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Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-4014-4741
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-4854-5531
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2017 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995Article in journal (Refereed) Epub ahead of print
Abstract [en]

MTH1 hydrolyzes oxidized nucleoside triphosphates, thereby sanitizing the nucleotide pool from oxidative damage. This prevents incorporation of damaged nucleotides into DNA, which otherwise would lead to mutations and cell death. The high level of reactive oxygen species in cancer cells leads to a higher level of oxidized nucleotides in cancer cells compared to non-malignant cells making cancer cells more dependent on MTH1 for survival. The possibility to specifically target cancer cells by inhibiting MTH1 has highlighted MTH1 as a promising cancer target. Progression of MTH1 inhibitors into the clinic requires animal studies and knowledge about species differences in potency of inhibitors are of vital importance. We here show that the human MTH1 inhibitor TH588 is approximately twenty fold less potent for inhibition of mouse MTH1 compared to human, rat, pig, and dog MTH1. We present the crystal structures of mouse MTH1 in complex with TH588 and dog MTH1and elucidate the structural and sequence basis for the observed difference in affinity for TH588. We identify amino acid residue 116 in MTH1 as an important determinant for TH588 affinity. Furthermore, we present the structure of mouse MTH1 in complex with the substrate 8-oxo-dGTP. The crystal structures provide insight into the high degree of structural conservation between MTH1 from different organisms and provide a detailed view of interactions between MTH1 and the inhibitor, revealing that minute structural differences can have a large impact on affinity and specificity.

Place, publisher, year, edition, pages
2017.
Keyword [en]
MTH1, MutT, Cancer biology, NUDT1, Inhibitor, TH588, 8-oxo-dGTP, oxidative stress, hydrolase, nucleoside/nucleotide analogue
National Category
Structural Biology Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-150682DOI: 10.1021/acs.biochem.7b01163OAI: oai:DiVA.org:su-150682DiVA: diva2:1170201
Funder
Swedish Research Council, 2014-5667Wenner-Gren FoundationsSwedish Cancer SocietyÅke Wiberg FoundationKnut and Alice Wallenberg Foundation
Available from: 2018-01-02 Created: 2018-01-02 Last updated: 2018-01-02
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