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PDBsum entry 6fmz
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References listed in PDB file
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Key reference
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Title
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Fragment-Based discovery of a regulatory site in thioredoxin glutathione reductase acting as "doorstop" for NADPH entry.
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Authors
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I.Silvestri,
H.Lyu,
F.Fata,
G.Boumis,
A.E.Miele,
M.Ardini,
R.Ippoliti,
A.Bellelli,
A.Jadhav,
W.A.Lea,
A.Simeonov,
Q.Cheng,
E.S.J.Arnér,
G.R.J.Thatcher,
P.A.Petukhov,
D.L.Williams,
F.Angelucci.
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Ref.
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ACS Chem Biol, 2018,
13,
2190-2202.
[DOI no: ]
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PubMed id
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Abstract
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Members of the FAD/NAD-linked reductase family are recognized as crucial targets
in drug development for cancers, inflammatory disorders, and infectious
diseases. However, individual FAD/NAD reductases are difficult to inhibit in a
selective manner with off-target inhibition reducing usefulness of identified
compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight
thioredoxin reductase-like enzyme, has emerged as a promising drug target for
the treatment of schistosomiasis, a parasitosis afflicting more than 200 million
people. Taking advantage of small molecules selected from a high-throughput
screen and using X-ray crystallography, functional assays, and docking studies,
we identify a critical secondary site of the enzyme. Compounds binding at this
site interfere with well-known and conserved conformational changes associated
with NADPH reduction, acting as a doorstop for cofactor entry. They selectively
inhibit TGR from Schistosoma mansoni and are active against parasites in
culture. Since many members of the FAD/NAD-linked reductase family have similar
catalytic mechanisms, the unique mechanism of inhibition identified in this
study for TGR broadly opens new routes to selectively inhibit homologous enzymes
of central importance in numerous diseases.
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