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PDBsum entry 5o2d
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Adp-ribose-binding-protein
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PDB id
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5o2d
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References listed in PDB file
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Key reference
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Title
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Discovery of a selective allosteric inhibitor targeting macrodomain 2 of polyadenosine-Diphosphate-Ribose polymerase 14.
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Authors
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M.Schuller,
K.Riedel,
I.Gibbs-Seymour,
K.Uth,
C.Sieg,
A.P.Gehring,
I.Ahel,
F.Bracher,
B.M.Kessler,
J.M.Elkins,
S.Knapp.
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Ref.
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ACS Chem Biol, 2017,
12,
2866-2874.
[DOI no: ]
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PubMed id
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Abstract
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Macrodomains are conserved protein interaction modules that can be found in all
domains of life including in certain viruses. Macrodomains mediate recognition
of sequence motifs harboring adenosine diphosphate ribose (ADPR) modifications,
thereby regulating a variety of cellular processes. Due to their role in cancer
or viral pathogenesis, macrodomains have emerged as potential therapeutic
targets, but the unavailability of small molecule inhibitors has hampered target
validation studies so far. Here, we describe an efficient screening strategy for
identification of small molecule inhibitors that displace ADPR from
macrodomains. We report the discovery and characterization of a macrodomain
inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low
micromolar affinity. Co-crystallization of a GeA-69 analogue with PARP14 MD2
revealed an allosteric binding mechanism explaining its selectivity over other
human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and
prevents its localization to sites of DNA damage.
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