Structural highlights
FunctionPublication Abstract from PubMedA 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 which 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 CDR-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 uPA. Biochemical analysis reveals that an intra-loop interaction network within the CDR-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. A Camelid-derived Antibody Fragment Targeting the Active Site of a Serine Protease Balances between Inhibitor and Substrate Behavior.,Kromann-Hansen T, Oldenburg E, Yung KW, Ghassabeh GH, Muyldermans S, Declerck PJ, Huang M, Andreasen PA, Ngo JC J Biol Chem. 2016 May 23. pii: jbc.M116.732503. PMID:27226628[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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