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PDBsum entry 5hgg
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Hydrolase/inhibitor
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PDB id
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5hgg
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References listed in PDB file
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Key reference
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Title
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A camelid-Derived antibody fragment targeting the active site of a serine protease balances between inhibitor and substrate behavior.
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Authors
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T.Kromann-Hansen,
E.Oldenburg,
K.W.Yung,
G.H.Ghassabeh,
S.Muyldermans,
P.J.Declerck,
M.Huang,
P.A.Andreasen,
J.C.Ngo.
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Ref.
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J Biol Chem, 2016,
291,
15156-15168.
[DOI no: ]
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PubMed id
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Abstract
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A peptide segment that binds the active site of a serine protease in a
substrate-like manner may behave like an inhibitor or a substrate. However,
there is sparse information on which factors determine the behavior a particular
peptide segment will exhibit. Here, we describe the first x-ray crystal
structure of a nanobody in complex with a serine protease. The nanobody displays
a new type of interaction between an antibody and a serine protease as it
inserts its complementary determining region-H3 loop into the active site of the
protease in a substrate-like manner. The unique binding mechanism causes the
nanobody to behave as a strong inhibitor as well as a poor substrate.
Intriguingly, its substrate behavior is incomplete, as 30-40% of the nanobody
remained intact and inhibitory after prolonged incubation with the protease.
Biochemical analysis reveals that an intra-loop interaction network within the
complementary determining region-H3 of the nanobody balances its inhibitor
versus substrate behavior. Collectively, our results unveil molecular factors,
which may be a general mechanism to determine the substrate versus inhibitor
behavior of other protease inhibitors.
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