title: Crystal structure of human MTH1 and the 8-oxo-dGMP product complex.
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.
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Svensson
authors.forename: Ann-Sofie
authors.initials: AS
authors.lastname: Jemth
authors.forename: Matthieu
authors.initials: M
authors.lastname: Desroses
authors.forename: Olga
authors.initials: O
authors.lastname: Loseva
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.forename: Martin
authors.initials: M
authors.lastname: Högbom
authors.forename: Pål
authors.initials: P
authors.lastname: Stenmark
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D003848:Deoxyguanine Nucleotides / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: C515742:8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-monophosphate; D003848:Deoxyguanine Nucleotides; C078206:8-oxodeoxyguanosine triphosphate; D006157:Guanosine Monophosphate; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes