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

► 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. MTH1...

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Bibliographic Details
Published in:FEBS letters 2011-08, Vol.585 (16), p.2617-2621
Main Authors: Svensson, Linda M., Jemth, Ann-Sofie, Desroses, Matthieu, Loseva, Olga, Helleday, Thomas, Högbom, Martin, Stenmark, Pål
Format: Article
Language:English
Subjects:
8-oxo-dGTP
8-oxo-dGTPase
Animals
Biochemistry
biokemi
Crystallography, X-Ray
Deoxyguanine Nucleotides - chemistry
Deoxyguanine Nucleotides - metabolism
DNA Repair Enzymes - antagonists & inhibitors
DNA Repair Enzymes - chemistry
DNA Repair Enzymes - metabolism
Drug Design
Guanosine Monophosphate - analogs & derivatives
Guanosine Monophosphate - chemistry
Guanosine Monophosphate - metabolism
Humans
Hydrogen Bonding
Mice
Models, Molecular
MTH1
MutT
NUDT1
Oxidation-Reduction
Oxidative damage
Phosphoric Monoester Hydrolases - antagonists & inhibitors
Phosphoric Monoester Hydrolases - chemistry
Phosphoric Monoester Hydrolases - metabolism
Protein Binding
Protein Conformation
Substrate Specificity
Tautomer
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Summary:► 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. 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.
ISSN:0014-5793
1873-3468
1873-3468
DOI:10.1016/j.febslet.2011.07.017