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PDBsum entry 4l6c
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Hydrolase/hydrolase inhibitor
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PDB id
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4l6c
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of human mitochondrial deoxyribonucleotidase in complex with the inhibitor pib-t
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Structure:
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5'(3')-deoxyribonucleotidase, mitochondrial. Chain: a. Fragment: unp residues 32-228. Synonym: 5',3'-nucleotidase, mitochondrial, deoxy-5'-nucleotidase 2, dnt-2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: dnt2, nt5m. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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1.80Å
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R-factor:
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0.151
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R-free:
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0.172
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Authors:
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P.Pachl,J.Brynda,P.Rezacova
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Key ref:
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O.Šimák
et al.
(2014).
Conformationally constrained nucleoside phosphonic acids--potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases.
Org Biomol Chem,
12,
7971-7982.
PubMed id:
DOI:
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Date:
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12-Jun-13
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Release date:
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10-Sep-14
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PROCHECK
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Headers
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References
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Q9NPB1
(NT5M_HUMAN) -
5'(3')-deoxyribonucleotidase, mitochondrial from Homo sapiens
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Seq:
Struc:
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228 a.a.
201 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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*
PDB and UniProt seqs differ
at 5 residue positions (black
crosses)
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DOI no:
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Org Biomol Chem
12:7971-7982
(2014)
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PubMed id:
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Conformationally constrained nucleoside phosphonic acids--potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases.
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O.Šimák,
P.Pachl,
M.Fábry,
M.Buděšínský,
T.Jandušík,
A.Hnízda,
R.Skleničková,
M.Petrová,
V.Veverka,
P.Řezáčová,
J.Brynda,
I.Rosenberg.
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ABSTRACT
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This work describes novel in vitro inhibitors of human mitochondrial (mdN) and
cytosolic (cdN) 5'(3')-deoxynucleotidases. We designed a series of derivatives
of the lead compound
(S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-β-d-threo-pentofuranosyl]thymine
bearing various substituents in the para position of the benzylidene moiety.
Detailed kinetic study revealed that certain para substituents increase the
inhibitory potency (iodo derivative; K = 2.71 μM) and some induce a shift in
selectivity toward cdN (carboxy derivative, K = 11.60 μM; iodoxy derivative, K
= 6.60 μM). Crystal structures of mdN in complex with three of these compounds
revealed that various para substituents lead to two alternative inhibitor
binding modes within the enzyme active site. Two binding modes were also
identified for cdN complexes by heteronuclear NMR spectroscopy.
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