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MTH1 Substrate Recognition--An Example of Specific Promiscuity.

J Willem M Nissink¹, Michal Bista², Jason Breed²

¹Chemistry, Oncology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Unit 310 (Darwin Building), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, United Kingdom, and Alderley Park, Cheshire, SK10 4TG, United Kingdom.

|March 22, 2016

Summary

Mutant enzyme homolog 1 (MTH1) prevents DNA damage. This study reveals MTH1’s intricate substrate recognition mechanism, highlighting water-mediated interactions crucial for selective binding and potential inhibitor design.

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Area of Science:

Biochemistry
Structural Biology
Medicinal Chemistry

Background:

Mutant enzyme homolog 1 (MTH1, also known as NUDT1) is a key enzyme in preventing DNA damage.
Understanding MTH1's substrate recognition is crucial for developing targeted cancer therapies.

Purpose of the Study:

To elucidate the substrate recognition mechanism of MTH1.
To present novel substrate-bound structures of MTH1.
To identify potential inhibitor binding modes for MTH1.

Main Methods:

Determined substrate-bound crystal structures of MTH1 with 8-oxo-dGTP and 8-oxo-rATP.
Utilized 2D Nuclear Magnetic Resonance (NMR) spectroscopy for fragment screening.
Obtained protein-ligand X-ray structures of MTH1 with identified fragments.

Main Results:

Identified novel strong and weak binding substrate motifs for MTH1.
Revealed alternative binding configurations of MTH1 through fragment screening.
Demonstrated MTH1's intricate and promiscuous substrate anchoring via its Asp-Asp pharmacophore.
Showcased the role of water-mediated interactions in conferring selectivity for oxidized substrates.

Conclusions:

MTH1 employs a complex mechanism for substrate binding, involving water molecules and the Asp-Asp motif.
Water-mediated hydrogen bonding in hydrophobic environments is key to MTH1's selectivity.
These findings provide a basis for the rational design of novel MTH1 inhibitors.