Digitala Vetenskapliga Arkivet

Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Engineered protease inhibitors based on sunflower trypsin inhibitor-1 (SFTI-1) provide insights into the role of sequence and conformation in Laskowski mechanism inhibition
Show others and affiliations
2015 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 469, no 2, p. 243-253Article in journal (Refereed) Published
Abstract [en]

Laskowski inhibitors regulate serine proteases by an intriguing mode of action that involves deceiving the protease into synthesizing a peptide bond. Studies exploring naturally occurring Laskowski inhibitors have uncovered several structural features that convey the inhibitor's resistance to hydrolysis and exceptional binding affinity. However, in the context of Laskowski inhibitor engineering, the way that various modifications intended to fine-tune an inhibitor's potency and selectivity impact on its association and dissociation rates remains unclear. This information is important as Laskowski inhibitors are becoming increasingly used as design templates to develop new protease inhibitors for pharmaceutical applications. In this study, we used the cyclic peptide, sunflower trypsin inhibitor-1 (SFTI-1), as a model system to explore how the inhibitor's sequence and structure relate to its binding kinetics and function. Using enzyme assays, MD simulations and NMR spectroscopy to study SFTI variants with diverse sequence and backbone modifications, we show that the geometry of the binding loop mainly influences the inhibitor's potency by modulating the association rate, such that variants lacking a favourable conformation show dramatic losses in activity. Additionally, we show that the inhibitor's sequence (including both the binding loop and its scaffolding) influences its potency and selectivity by modulating both the association and the dissociation rates. These findings provide new insights into protease inhibitor function and design that we apply by engineering novel inhibitors for classical serine proteases, trypsin and chymotrypsin and two kallikrein-related peptidases (KLK5 and KLK14) that are implicated in various cancers and skin diseases.

Place, publisher, year, edition, pages
2015. Vol. 469, no 2, p. 243-253
Keywords [en]
cyclic peptides, drug design, kallikrein-related peptidase, Laskowski mechanism, protease inhibitors
National Category
Medical Bioscience
Identifiers
URN: urn:nbn:se:umu:diva-109817DOI: 10.1042/BJ20150412ISI: 000361051800009PubMedID: 25981970Scopus ID: 2-s2.0-84937113459OAI: oai:DiVA.org:umu-109817DiVA, id: diva2:859475
Available from: 2015-10-07 Created: 2015-10-06 Last updated: 2023-03-24Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMedScopus

Search in DiVA

By author/editor
Brattsand, Maria
By organisation
Department of Medical Biosciences
In the same journal
Biochemical Journal
Medical Bioscience

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 863 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf