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PDBsum entry 6wlc
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Viral protein
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PDB id
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6wlc
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References listed in PDB file
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Key reference
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Title
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Tipiracil binds to uridine site and inhibits nsp15 endoribonuclease nendou from sars-Cov-2.
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Authors
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Y.Kim,
J.Wower,
N.Maltseva,
C.Chang,
R.Jedrzejczak,
M.Wilamowski,
S.Kang,
V.Nicolaescu,
G.Randall,
K.Michalska,
A.Joachimiak.
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Ref.
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Commun Biol, 2021,
4,
193.
[DOI no: ]
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PubMed id
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Abstract
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SARS-CoV-2 Nsp15 is a uridine-specific endoribonuclease with C-terminal
catalytic domain belonging to the EndoU family that is highly conserved in
coronaviruses. As endoribonuclease activity seems to be responsible for the
interference with the innate immune response, Nsp15 emerges as an attractive
target for therapeutic intervention. Here we report the first structures with
bound nucleotides and show how the enzyme specifically recognizes uridine
moiety. In addition to a uridine site we present evidence for a second base
binding site that can accommodate any base. The structure with a transition
state analog, uridine vanadate, confirms interactions key to catalytic
mechanisms. In the presence of manganese ions, the enzyme cleaves unpaired RNAs.
This acquired knowledge was instrumental in identifying Tipiracil, an FDA
approved drug that is used in the treatment of colorectal cancer, as a potential
anti-COVID-19 drug. Using crystallography, biochemical, and whole-cell assays,
we demonstrate that Tipiracil inhibits SARS-CoV-2 Nsp15 by interacting with the
uridine binding pocket in the enzyme's active site. Our findings provide new
insights for the development of uracil scaffold-based drugs.
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