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PDBsum entry 4l7o
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Transferase/transferase inhibitor
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PDB id
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4l7o
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Human artd3 (parp3) - catalytic domain in complex with inhibitor sto1542
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Structure:
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Poly [adp-ribose] polymerase 3. Chain: a. Fragment: catalytic parp domain. Synonym: parp-3, hparp-3, adp-ribosyltransferase diphtheria toxin- like 3, artd3, irt1, NAD(+) adp-ribosyltransferase 3, adprt-3, poly[adp-ribose] synthase 3, padprt-3. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: adprt3, adprtl3, parp3. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.00Å
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R-factor:
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0.165
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R-free:
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0.210
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Authors:
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T.Karlberg,A.G.Thorsell,A.E.G.Lindgren,T.Ekblad,S.Spjut, C.D.Andersson,J.Weigelt,A.Linusson,M.Elofsson,H.Schuler
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Key ref:
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A.E.Lindgren
et al.
(2013).
Chemical probes to study ADP-ribosylation: synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3.
J Med Chem,
56,
9556-9568.
PubMed id:
DOI:
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Date:
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14-Jun-13
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Release date:
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19-Feb-14
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PROCHECK
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Headers
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References
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Q9Y6F1
(PARP3_HUMAN) -
Protein mono-ADP-ribosyltransferase PARP3 from Homo sapiens
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Seq:
Struc:
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533 a.a.
354 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 2 residue positions (black
crosses)
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DOI no:
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J Med Chem
56:9556-9568
(2013)
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PubMed id:
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Chemical probes to study ADP-ribosylation: synthesis and biochemical evaluation of inhibitors of the human ADP-ribosyltransferase ARTD3/PARP3.
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A.E.Lindgren,
T.Karlberg,
T.Ekblad,
S.Spjut,
A.G.Thorsell,
C.D.Andersson,
T.T.Nhan,
V.Hellsten,
J.Weigelt,
A.Linusson,
H.Schüler,
M.Elofsson.
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ABSTRACT
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The racemic
3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1,
has previously been identified as a potent but unselective inhibitor of
diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe
synthesis and evaluation of 55 compounds in this class. It was found that the
stereochemistry is of great importance for both selectivity and potency and that
substituents on the phenyl ring resulted in poor solubility. Certain variations
at the meso position were tolerated and caused a large shift in the binding
pose. Changes to the ethylene linker that connects the quinazolinone to the
amide were also investigated but proved detrimental to binding. By combination
of synthetic organic chemistry and structure-based design, two selective
inhibitors of ARTD3 were discovered.
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