A Camelid-derived Antibody Fragment Targeting the Active Site of a Serine Protease Balances between Inhibitor and Substrate Behavior
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AbstractA 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 remainedintactandinhibitoryafterprolongedincubationwiththe 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.
All Author(s) ListKromann-Hansen T, Oldenburg E, Yung KWY, Ghassabeh GH, Muyldermans S, Declerck PJ, Huang MD, Andreasen PA, Ngo JCK
Journal nameJournal of Biological Chemistry,Journal of Biological Chemistry
Detailed descriptionVolume 291, number 29
Year2016
Month7
Day15
Volume Number291
Issue Number29
PublisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Pages15156 - 15168
ISSN0021-9258
eISSN1083-351X
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesBiochemistry & Molecular Biology

Last updated on 2020-04-04 at 11:26