Crystal structure of human MTH1 and the 8-oxo-dGMP product complex

MTH1 hydrolyzes oxidized nucleotide triphosphates, thereby preventing them from being incorporated into DNA. We here present the structures of human MTH1 (1.9 Å) and its complex with the product 8-oxo-dGMP (1.8 Å). Unexpectedly MTH1 binds the nucleotide in the anti conformation with no direct interaction between the 8-oxo group and the protein. We suggest that the specificity depends on the stabilization of an enol tautomer of the 8-oxo form of dGTP. The binding of the product induces no major structural changes. The structures reveal the mode of nucleotide binding in MTH1 and provide the structural basis for inhibitor design.

► We have determined the structures of human MTH1 and its product complex.
► There are no direct interactions between the 8-oxo group and the protein.
► The structures reveal the mode of nucleotide binding in MTH1.
► Surprisingly, MTH1 has a substrate recognition mechanism, distinct from MutT.