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Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors

  • Simon J. de Veer , Joakim E. Swedberg , Maria Brattsand , Judith A. Clements and Jonathan M. Harris EMAIL logo
Published/Copyright: February 19, 2016
Biological Chemistry
From the journal Biological Chemistry Volume 397 Issue 12

Abstract

Kallikrein-related peptidase 5 (KLK5) is a promising therapeutic target in several skin diseases, including Netherton syndrome, and is emerging as a potential target in various cancers. In this study, we used a sparse matrix library of 125 individually synthesized peptide substrates to characterize the binding specificity of KLK5. The sequences most favored by KLK5 were GRSR, YRSR and GRNR, and we identified sequence-specific interactions involving the peptide N-terminus by analyzing kinetic constants (kcat and KM) and performing molecular dynamics simulations. KLK5 inhibitors were subsequently engineered by substituting substrate sequences into the binding loop (P1, P2 and P4 residues) of sunflower trypsin inhibitor-1 (SFTI-1). These inhibitors were effective against KLK5 but showed limited selectivity, and performing a further substitution at P2′ led to the design of a new variant that displayed improved activity against KLK5 (Ki=4.2±0.2 nm), weak activity against KLK7 and 12-fold selectivity over KLK14. Collectively, these findings provide new insight into the design of highly favored binding sequences for KLK5 and reveal several opportunities for modulating inhibitor selectivity over closely related proteases that will be useful for future studies aiming to develop therapeutic molecules targeting KLK5.

Keywords: inhibitor engineering; peptide; serine protease; sparse matrix library; sunflower trypsin inhibitor-1

Acknowledgments

This work was supported by the Australian National Health and Medical Research Council (NHMRC) (grant 1059410). J.S. is a NHMRC Early Career Fellow (grant 1069819).

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Received: 2016-1-13
Accepted: 2016-2-16
Published Online: 2016-2-19
Published in Print: 2016-12-1

©2016 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: remodelling the KLK landscape down under
  4. HIGHLIGHT: 6TH INTERNATIONAL SYMPOSIUM ON KALLIKREINS AND KALLIKREIN-RELATED PEPTIDASES
  5. Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications
  6. Mechanistic insight from murine models of Netherton syndrome
  7. Development of molecules stimulating the activity of KLK3 – an update
  8. Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors
  9. Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10
  10. Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer
  11. Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
  12. A viable mouse model for Netherton syndrome based on mosaic inactivation of the Spink5 gene
  13. Therapeutic modulation of tissue kallikrein expression
  14. In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B
  15. A computational analysis of the genetic and transcript diversity at the kallikrein locus
  16. Reviews
  17. Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome
  18. The power, pitfalls and potential of the nanodisc system for NMR-based studies
  19. Research Articles/Short Communications
  20. Cell Biology and Signaling
  21. Synergistic induction of cardiomyocyte differentiation from human bone marrow mesenchymal stem cells by interleukin 1β and 5-azacytidine
https://doi.org/10.1515/hsz-2016-0112
Keywords for this article
inhibitor engineering; peptide; serine protease; sparse matrix library; sunflower trypsin inhibitor-1

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: remodelling the KLK landscape down under
  4. HIGHLIGHT: 6TH INTERNATIONAL SYMPOSIUM ON KALLIKREINS AND KALLIKREIN-RELATED PEPTIDASES
  5. Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications
  6. Mechanistic insight from murine models of Netherton syndrome
  7. Development of molecules stimulating the activity of KLK3 – an update
  8. Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors
  9. Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10
  10. Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer
  11. Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
  12. A viable mouse model for Netherton syndrome based on mosaic inactivation of the Spink5 gene
  13. Therapeutic modulation of tissue kallikrein expression
  14. In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B
  15. A computational analysis of the genetic and transcript diversity at the kallikrein locus
  16. Reviews
  17. Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome
  18. The power, pitfalls and potential of the nanodisc system for NMR-based studies
  19. Research Articles/Short Communications
  20. Cell Biology and Signaling
  21. Synergistic induction of cardiomyocyte differentiation from human bone marrow mesenchymal stem cells by interleukin 1β and 5-azacytidine
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