A Camelid-derived Antibody Fragment Targeting the Active Site of a Serine Protease Balances between Inhibitor and Substrate Behavior
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香港中文大學研究人員

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摘要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 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.
著者Kromann-Hansen T, Oldenburg E, Yung KWY, Ghassabeh GH, Muyldermans S, Declerck PJ, Huang MD, Andreasen PA, Ngo JCK
期刊名稱Journal of Biological Chemistry,Journal of Biological Chemistry
詳細描述Volume 291, number 29
出版年份2016
月份7
日期15
卷號291
期次29
出版社AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
頁次15156 - 15168
國際標準期刊號0021-9258
電子國際標準期刊號1083-351X
語言英式英語
Web of Science 學科類別Biochemistry & Molecular Biology

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