MTH1 Substrate Recognition--An Example of Specific Promiscuity

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.