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PDBsum entry 4lh6
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Ligase/ligase inhibitor
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PDB id
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4lh6
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PDB id:
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| Name: |
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Ligase/ligase inhibitor
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Title:
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Crystal structure of a liga inhibitor
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Structure:
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DNA ligase. Chain: a. Fragment: adenylation domain, unp residues 1-323. Synonym: polydeoxyribonucleotide synthase [nad(+)]. Engineered: yes
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Source:
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Enterococcus faecalis. Organism_taxid: 226185. Strain: atcc 700802 / v583. Gene: liga, ef_0722. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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1.65Å
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R-factor:
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0.221
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R-free:
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0.248
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Authors:
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K.Benenato,H.Wang,H.M.Mcguire,H.Davis,N.Gao,D.B.Prince,H.Jahic, S.S.Stokes,P.A.Boriack-Sjodin
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Key ref:
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K.Murphy-Benenato
et al.
(2014).
Identification through structure-based methods of a bacterial NAD(+)-dependent DNA ligase inhibitor that avoids known resistance mutations.
Bioorg Med Chem Lett,
24,
360-366.
PubMed id:
DOI:
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Date:
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30-Jun-13
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Release date:
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25-Dec-13
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PROCHECK
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Headers
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References
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Q837V6
(DNLJ_ENTFA) -
DNA ligase from Enterococcus faecalis (strain ATCC 700802 / V583)
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Seq:
Struc:
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676 a.a.
322 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:
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E.C.6.5.1.2
- Dna ligase (NAD(+)).
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Reaction:
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NAD+ + (deoxyribonucleotide)n-3'-hydroxyl + 5'-phospho- (deoxyribonucleotide)m = (deoxyribonucleotide)n+m + AMP + beta- nicotinamide D-nucleotide
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NAD(+)
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+
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(deoxyribonucleotide)n-3'-hydroxyl
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+
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5'-phospho- (deoxyribonucleotide)m
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=
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(deoxyribonucleotide)n+m
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AMP
Bound ligand (Het Group name = )
matches with 73.08% similarity
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+
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beta- nicotinamide D-nucleotide
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Bioorg Med Chem Lett
24:360-366
(2014)
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PubMed id:
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Identification through structure-based methods of a bacterial NAD(+)-dependent DNA ligase inhibitor that avoids known resistance mutations.
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K.Murphy-Benenato,
H.Wang,
H.M.McGuire,
H.E.Davis,
N.Gao,
D.B.Prince,
H.Jahic,
S.S.Stokes,
P.A.Boriack-Sjodin.
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ABSTRACT
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In an attempt to identify novel inhibitors of NAD(+)-dependent DNA ligase (LigA)
that are not affected by a known resistance mutation in the adenosine binding
pocket, a detailed analysis of the binding sites of a variety of bacterial
ligases was performed. This analysis revealed several similarities to the
adenine binding region of kinases, which enabled a virtual screen of known
kinase inhibitors. From this screen, a thienopyridine scaffold was identified
that was shown to inhibit bacterial ligase. Further characterization through
structure and enzymology revealed the compound was not affected by a previously
disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A
subsequent medicinal chemistry program identified substitutions that resulted in
an inhibitor with moderate activity across various Gram-positive bacterial LigA
enzymes.
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