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Crystal structure of human MTH1 and the 8-oxo-dGMP product complex
Linda M Svensson1, Ann-Sofie Jemth, Matthieu Desroses
1Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
Abstract:
MTH1 hydrolyzes oxidized nucleotide triphosphates, thereby preventing them from being incorporated into DNA. We here present the structures of human MTH1 (1.9Å) and its complex with the product 8-oxo-dGMP (1.8Å). 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.
Insights
Human MTH1 enzyme prevents DNA damage by hydrolyzing oxidized nucleotides. Its structure reveals an unexpected binding mode, crucial for designing new inhibitors to prevent DNA damage.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Oxidized nucleotide triphosphates can be incorporated into DNA, leading to mutations.
- MTH1 (NUDIX hydrolase) hydrolyzes these damaged nucleotides, protecting genomic integrity.
Purpose of the Study:
- To determine the high-resolution crystal structures of human MTH1.
- To elucidate the mechanism of nucleotide binding and product recognition by MTH1.
- To provide a structural foundation for developing MTH1-targeted inhibitors.
Main Methods:
- X-ray crystallography was used to determine the structures of human MTH1 and its complex with 8-oxo-dGMP.
- Analysis of protein-nucleotide interactions at atomic resolution.
Main Results:
- The crystal structure of human MTH1 was determined at 1.9Å resolution.
- The structure of the MTH1-8-oxo-dGMP complex was solved at 1.8Å resolution.
- MTH1 binds 8-oxo-dGMP in an anti conformation, with specificity potentially arising from stabilizing an enol tautomer, not direct interaction with the 8-oxo group.
Conclusions:
- The determined structures reveal the precise mode of nucleotide binding by MTH1.
- Understanding the binding mechanism provides a structural basis for rational inhibitor design against MTH1.
- This research contributes to strategies for preventing DNA damage caused by oxidized nucleotides.
