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PDBsum entry 5fsl
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PDB id:
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Hydrolase
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Title:
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Mth1 substrate recognition: complex with a methylaminopurinone
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Structure:
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7,8-dihydro-8-oxoguanine triphosphatase. Chain: a. Fragment: yes, unp residues 42-197. Synonym: 2-hydroxy-datp diphosphatase, 8-oxo-dgtpase, nucleoside diphosphate-linked moiety x motif 1, nudix motif 1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.24Å
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R-factor:
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0.202
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R-free:
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0.212
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Authors:
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J.W.M.Nissink,M.Bista,J.Breed,N.Carter,K.Embrey,J.Read,C.Phillips, J.J.Winter
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Key ref:
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J.W.Nissink
et al.
(2016).
MTH1 Substrate Recognition--An Example of Specific Promiscuity.
Plos One,
11,
e0151154.
PubMed id:
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Date:
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06-Jan-16
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Release date:
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20-Jul-16
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PROCHECK
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Headers
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References
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P36639
(8ODP_HUMAN) -
Oxidized purine nucleoside triphosphate hydrolase from Homo sapiens
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Seq:
Struc:
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156 a.a.
154 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class 2:
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E.C.3.6.1.-
- ?????
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Enzyme class 3:
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E.C.3.6.1.56
- 2-hydroxy-dATP diphosphatase.
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Reaction:
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2-oxo-dATP + H2O = 2-oxo-dAMP + diphosphate + H+
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2-oxo-dATP
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+
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H2O
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=
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2-oxo-dAMP
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+
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diphosphate
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+
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H(+)
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Plos One
11:e0151154
(2016)
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PubMed id:
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MTH1 Substrate Recognition--An Example of Specific Promiscuity.
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J.W.Nissink,
M.Bista,
J.Breed,
N.Carter,
K.Embrey,
J.Read,
J.J.Winter-Holt.
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ABSTRACT
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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.
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Links
