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

FEBS Lett. 2011 Aug 19;585(16):2617-21. doi: 10.1016/j.febslet.2011.07.017. Epub 2011 Jul 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • DNA Repair Enzymes / antagonists & inhibitors
  • DNA Repair Enzymes / chemistry*
  • DNA Repair Enzymes / metabolism*
  • Deoxyguanine Nucleotides / chemistry
  • Deoxyguanine Nucleotides / metabolism
  • Drug Design
  • Guanosine Monophosphate / analogs & derivatives*
  • Guanosine Monophosphate / chemistry
  • Guanosine Monophosphate / metabolism
  • Humans
  • Hydrogen Bonding
  • Mice
  • Models, Molecular
  • Oxidation-Reduction
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Phosphoric Monoester Hydrolases / chemistry*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Protein Binding
  • Protein Conformation
  • Substrate Specificity

Substances

  • 8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-monophosphate
  • Deoxyguanine Nucleotides
  • 8-oxodeoxyguanosine triphosphate
  • Guanosine Monophosphate
  • Phosphoric Monoester Hydrolases
  • 8-oxodGTPase
  • DNA Repair Enzymes