Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics

Riley, Blake T., Ilyichova, Olga, Costa, Mauricio G. S., Porebski, Benjamin T., De Veer, Simon J., Swedberg, Joakim E., Kass, Itamar, Harris, Jonathan M., Hoke, David E. and Buckle, Ashley M. (2016) Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics. Scientific Reports, 6 . doi:10.1038/srep35385

Author Riley, Blake T.
Ilyichova, Olga
Costa, Mauricio G. S.
Porebski, Benjamin T.
De Veer, Simon J.
Swedberg, Joakim E.
Kass, Itamar
Harris, Jonathan M.
Hoke, David E.
Buckle, Ashley M.
Title Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2016-10-21
Year available 2016
Sub-type Article (original research)
DOI 10.1038/srep35385
Open Access Status DOI
Volume 6
Total pages 14
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1000 General
Abstract The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (∼1 Å) resolution, as well as with bound nickel. These structures offer a structural rationalization for the potency and selectivity of these inhibitors, and together with MD simulation and computational analysis, reveal a dynamic pathway between the metal binding exosite and the active site, providing key details of a previously proposed allosteric mode of inhibition. Collectively, this work provides insight into both direct and indirect mechanisms of inhibition for KLK4 that have broad implications for the enzymology of the serine protease superfamily, and may potentially be exploited for the design of therapeutic inhibitors.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1069819
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
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