A versatile and robust serine protease inhibitor scaffold from Actinia tenebrosa
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Description
Serine proteases play pivotal roles in normal physiology and a spectrum of patho-physiological processes. Accordingly, there is considerable interest in the discovery and design of potent serine protease inhibitors for therapeutic applications. This led to concerted efforts to discover versatile and robust molecular scaffolds for inhibitor design. This investigation is a bioprospecting study that aims to isolate and identify protease inhibitors from the cnidarian Actinia tenebrosa. The study isolated two Kunitz-type protease inhibitors with very similar sequences but quite divergent inhibitory potencies when assayed against bovine trypsin, chymostrypsin, and a selection of human sequence-related peptidases. Homology modeling and molecular dynamics simulations of these inhibitors in complex with their targets were carried out and, collectively, these methodologies enabled the definition of a versatile scaffold for inhibitor design. Thermal denaturation studies showed that the inhibitors were remarkably robust. To gain a fine-grained map of the residues responsible for this stability, we conducted in silico alanine scanning and quantified individual residue contributions to the inhibitor’s stability. Sequences of these inhibitors were then used to search for Kunitz homologs in an A. tenebrosa transcriptome library, resulting in the discovery of a further 14 related sequences. Consensus analysis of these variants identified a rich molecular diversity of Kunitz domains and expanded the palette of potential residue substitutions for rational inhibitor design using this domain.
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ID Code: | 197348 | ||||||||||
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Item Type: | Contribution to Journal (Journal Article) | ||||||||||
Refereed: | Yes | ||||||||||
ORCID iD: |
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Measurements or Duration: | 21 pages | ||||||||||
Keywords: | Actinia tenebrosa, Kunitz inhibitor, kallikrein-related peptidases, mass spectrometry imaging, molecular dynamics simulation, serine protease, Kallikrein‐related peptidases, Mass spectrometry imaging, Serine protease, Molecular dynamics simulation | ||||||||||
DOI: | 10.3390/md17120701 | ||||||||||
ISSN: | 1660-3397 | ||||||||||
Pure ID: | 39395447 | ||||||||||
Divisions: | Past > QUT Faculties & Divisions > Faculty of Health Past > Institutes > Institute of Health and Biomedical Innovation Past > QUT Faculties & Divisions > Science & Engineering Faculty |
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Funding: | |||||||||||
Copyright Owner: | Consult author(s) regarding copyright matters | ||||||||||
Copyright Statement: | This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au | ||||||||||
Deposited On: | 10 Mar 2020 01:41 | ||||||||||
Last Modified: | 01 Mar 2024 19:58 |
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