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MTH1 Substrate Recognition--An Example of Specific Promiscuity.
- Source :
-
PloS one [PLoS One] 2016 Mar 21; Vol. 11 (3), pp. e0151154. Date of Electronic Publication: 2016 Mar 21 (Print Publication: 2016). - Publication Year :
- 2016
-
Abstract
- MTH1 (NUDT1) is an oncologic target involved in the prevention of DNA damage. We investigate the way MTH1 recognises its substrates and present substrate-bound structures of MTH1 for 8-oxo-dGTP and 8-oxo-rATP as examples of novel strong and weak binding substrate motifs. Investigation of a small set of purine-like fragments using 2D NMR resulted in identification of a fragment with weak potency. The protein-ligand X-Ray structure of this fragment provides insight into the role of water molecules in substrate selectivity. Wider fragment screening by NMR resulted in three new protein structures exhibiting alternative binding configurations to the key Asp-Asp recognition element of the protein. These inhibitor binding modes demonstrate that MTH1 employs an intricate yet promiscuous mechanism of substrate anchoring through its Asp-Asp pharmacophore. The structures suggest that water-mediated interactions convey selectivity towards oxidized substrates over their non-oxidised counterparts, in particular by stabilization of a water molecule in a hydrophobic environment through hydrogen bonding. These findings may be useful in the design of inhibitors of MTH1.
- Subjects :
- Amino Acid Motifs
Aspartic Acid metabolism
Binding Sites
Crystallography, X-Ray
Deoxyguanine Nucleotides chemistry
Deoxyguanine Nucleotides metabolism
Hydrogen Bonding
Kinetics
Magnetic Resonance Spectroscopy
Phosphoric Monoester Hydrolases chemistry
Protein Structure, Secondary
Substrate Specificity
Water
Phosphoric Monoester Hydrolases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 11
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 26999531
- Full Text :
- https://doi.org/10.1371/journal.pone.0151154