1iry
From Proteopedia
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[[Image:1iry.gif|left|200px]] | [[Image:1iry.gif|left|200px]] | ||
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'''Solution structure of the hMTH1, a nucleotide pool sanitization enzyme''' | '''Solution structure of the hMTH1, a nucleotide pool sanitization enzyme''' | ||
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[[Category: Sakai, Y.]] | [[Category: Sakai, Y.]] | ||
[[Category: Shirakawa, M.]] | [[Category: Shirakawa, M.]] | ||
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Revision as of 17:20, 2 May 2008
Solution structure of the hMTH1, a nucleotide pool sanitization enzyme
Overview
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.
About this Structure
1IRY is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structure of human MTH1, a Nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates., Mishima M, Sakai Y, Itoh N, Kamiya H, Furuichi M, Takahashi M, Yamagata Y, Iwai S, Nakabeppu Y, Shirakawa M, J Biol Chem. 2004 Aug 6;279(32):33806-15. Epub 2004 May 7. PMID:15133035 Page seeded by OCA on Fri May 2 20:20:32 2008
