Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• MTH1 sanitizes the nucleotide pool by hydrolyzing oxidized nucleoside triphosphates, preventing DNA damage and mutations.
• Cancer cells exhibit higher oxidative stress and increased reliance on MTH1 for survival, making it a promising cancer target.
• Inhibiting MTH1 is a potential therapeutic strategy, necessitating understanding of species-specific drug efficacy for preclinical studies.

Purpose of the Study:

• To investigate species differences in MTH1 protein inhibition by the drug TH588.
• To elucidate the structural basis for varying inhibitor potency across species.
• To provide insights into MTH1-inhibitor interactions for drug development.

Main Methods:

• Determined crystal structures of mouse MTH1 with TH588 and dog MTH1 with TH588.
• Analyzed structural and sequence variations in MTH1 proteins.
• Presented the crystal structure of mouse MTH1 with its substrate 8-oxo-dGTP.

Main Results:

• The MTH1 inhibitor TH588 was approximately 20-fold less potent against mouse MTH1 compared to human, rat, pig, and dog MTH1.
• Amino acid residue 116 in MTH1 was identified as a key determinant of TH588 affinity.
• Structural analysis revealed high conservation among MTH1 proteins, with minor differences impacting inhibitor binding.

Conclusions:

• Minute structural variations in MTH1 significantly affect inhibitor affinity and specificity across species.
• Understanding these species-specific differences is crucial for advancing MTH1 inhibitors into clinical applications.
• The study provides a structural basis for rational drug design targeting MTH1.