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Crystal structure of human MTH1 and the 8‐oxo‐dGMP product complex
Author(s) -
Svensson Linda M.,
Jemth Ann-Sofie,
Desroses Matthieu,
Loseva Olga,
Helleday Thomas,
Högbom Martin,
Stenmark Pål
Publication year - 2011
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2011.07.017
Subject(s) - nucleotide , chemistry , tautomer , dna , stereochemistry , hydrolysis , biochemistry , gene
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.