6QVO

Crystal structure of human MTH1 in complex with N6-methyl-dAMP

Summary for 6QVO

• Entry DOI: 10.2210/pdb6qvo/pdb
• Descriptor: 7,8-dihydro-8-oxoguanine triphosphatase, SULFATE ION, N6-METHYL-DEOXY-ADENOSINE-5'-MONOPHOSPHATE, ... (5 entities in total)
• Functional Keywords: ----, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 92223.73

Authors

Scaletti, E.,Vallin, K.S.,Brautigam, L.,Sarno, A.,Warpman Berglund, U.,Helleday, T.,Stenmark, P.,Jemth, A.S. (deposition date: 2019-03-04, release date: 2020-03-18, Last modification date: 2024-05-15)

Primary citation

Scaletti, E.R.,Vallin, K.S.,Brautigam, L.,Sarno, A.,Warpman Berglund, U.,Helleday, T.,Stenmark, P.,Jemth, A.S.
MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool.
J.Biol.Chem., 295:4761-4772, 2020

PubMed Abstract: MutT homologue 1 (MTH1) removes oxidized nucleotides from the nucleotide pool and thereby prevents their incorporation into the genome and thereby reduces genotoxicity. We previously reported that MTH1 is an efficient catalyst of O6-methyl-dGTP hydrolysis suggesting that MTH1 may also sanitize the nucleotide pool from other methylated nucleotides. We here show that MTH1 efficiently catalyzes the hydrolysis of N6-methyl-dATP to N6-methyl-dAMP and further report that N6-methylation of dATP drastically increases the MTH1 activity. We also observed MTH1 activity with N6-methyl-ATP, albeit at a lower level. We show that N6-methyl-dATP is incorporated into DNA , as indicated by increased N6-methyl-dA DNA levels in embryos developed from MTH1 knock-out zebrafish eggs microinjected with N6-methyl-dATP compared with noninjected embryos. N6-methyl-dATP activity is present in MTH1 homologues from distantly related vertebrates, suggesting evolutionary conservation and indicating that this activity is important. Of note, N6-methyl-dATP activity is unique to MTH1 among related NUDIX hydrolases. Moreover, we present the structure of N6-methyl-dAMP-bound human MTH1, revealing that the N6-methyl group is accommodated within a hydrophobic active-site subpocket explaining why N6-methyl-dATP is a good MTH1 substrate. N6-methylation of DNA and RNA has been reported to have epigenetic roles and to affect mRNA metabolism. We propose that MTH1 acts in concert with adenosine deaminase-like protein isoform 1 (ADAL1) to prevent incorporation of N6-methyl-(d)ATP into DNA and RNA. This would hinder potential dysregulation of epigenetic control and RNA metabolism via conversion of N6-methyl-(d)ATP to N6-methyl-(d)AMP, followed by ADAL1-catalyzed deamination producing (d)IMP that can enter the nucleotide salvage pathway.

PubMed: 32144205
DOI: 10.1074/jbc.RA120.012636

Experimental method

X-RAY DIFFRACTION (2.45 Å)