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A substrate-driven allosteric switch that enhances PDI catalytic activity
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Journal Article
A substrate-driven allosteric switch that enhances PDI catalytic activity
2016
Overview
Protein disulfide isomerase (PDI) is an oxidoreductase essential for folding proteins in the endoplasmic reticulum. The domain structure of PDI is
a
–
b
–
b′
–
x
–
a′
, wherein the thioredoxin-like
a
and
a′
domains mediate disulfide bond shuffling and
b
and
b′
domains are substrate binding. The
b′
and
a′
domains are connected via the x-linker, a 19-amino-acid flexible peptide. Here we identify a class of compounds, termed bepristats, that target the substrate-binding pocket of
b′
. Bepristats reversibly block substrate binding and inhibit platelet aggregation and thrombus formation
in vivo
. Ligation of the substrate-binding pocket by bepristats paradoxically enhances catalytic activity of
a
and
a′
by displacing the x-linker, which acts as an allosteric switch to augment reductase activity in the catalytic domains. This substrate-driven allosteric switch is also activated by peptides and proteins and is present in other thiol isomerases. Our results demonstrate a mechanism whereby binding of a substrate to thiol isomerases enhances catalytic activity of remote domains.
Protein Disulfide Isomerase (PDI) is a prothrombotic, multidomain enzyme with separate substrate binding and catalytic domains. Here, the authors identify a new class of compounds that target the PDI substrate binding site, inducing a conformational change in the catalytic domains and inhibiting thrombosis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
