1IRY

Solution structure of the hMTH1, a nucleotide pool sanitization enzyme

Summary for 1IRY

• Entry DOI: 10.2210/pdb1iry/pdb
• Descriptor: hMTH1 (1 entity in total)
• Functional Keywords: nudix motif(g37-l59), hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 17971.46

Authors

Mishima, M.,Itoh, N.,Sakai, Y.,Kamiya, H.,Nakabeppu, Y.,Shirakawa, M. (deposition date: 2001-10-25, release date: 2003-12-23, Last modification date: 2023-12-27)

Primary citation

Mishima, M.,Sakai, Y.,Itoh, N.,Kamiya, H.,Furuichi, M.,Takahashi, M.,Yamagata, Y.,Iwai, S.,Nakabeppu, Y.,Shirakawa, M.
Structure of human MTH1, a Nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates
J.Biol.Chem., 279:33806-33815, 2004

PubMed Abstract: Oxygen radicals generated through normal cellular respiration processes can cause mutations in genomic and mitochondrial DNA. Human MTH1 hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-dATP, to monophosphates, thereby preventing the misincorporation of these oxidized nucleotides during replication. Here we present the solution structure of MTH1 solved by multidimensional heteronuclear NMR spectroscopy. The protein adopts a fold similar to that of Escherichia coli MutT, despite the low sequence similarity between these proteins outside the conserved Nudix motif. The substrate-binding pocket of MTH1, deduced from chemical shift perturbation experiments, is located at essentially the same position as in MutT; however, a pocket-forming helix is largely displaced in MTH1 (approximately 9 A) such that the shape of the pocket differs between the two proteins. Detailed analysis of the pocket-forming residues enabled us to identify Asn33 as one of the key residues in MTH1 for discriminating the oxidized form of purine, and mutation of this residue modifies the substrate specificity. We also show that MTH1 catalyzes hydrolysis of 8-oxo-dGTP through nucleophilic substitution of water at the beta-phosphate.

PubMed: 15133035
DOI: 10.1074/jbc.M402393200

Experimental method

SOLUTION NMR