A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods

Marko Novinec, Matevž Korenč, Amedeo Caflisch, Rama Ranganathan, Brigita Lenarčič, Antonio Baici

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Allosteric modifiers have the potential to fine-tune enzyme activity. Therefore, targeting allosteric sites is gaining increasing recognition as a strategy in drug design. Here we report the use of computational methods for the discovery of the first small-molecule allosteric inhibitor of the collagenolytic cysteine peptidase cathepsin K, a major target for the treatment of osteoporosis. The molecule NSC13345 is identified by high-throughput docking of compound libraries to surface sites on the peptidase that are connected to the active site by an evolutionarily conserved network of residues (protein sector). The crystal structure of the complex shows that NSC13345 binds to a novel allosteric site on cathepsin K. The compound acts as a hyperbolic mixed modifier in the presence of a synthetic substrate, it completely inhibits collagen degradation and has good selectivity for cathepsin K over related enzymes. Altogether, these properties qualify our methodology and NSC13345 as promising candidates for allosteric drug design.

Original languageEnglish (US)
Pages (from-to)3287
Number of pages1
JournalNature Communications
Volume5
DOIs
StatePublished - 2014

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Cathepsin K
cysteine
Computational methods
Allosteric Site
Cysteine
drugs
Peptide Hydrolases
Drug Design
osteoporosis
enzyme activity
collagens
inhibitors
enzymes
molecules
Molecules
sectors
selectivity
Enzyme activity
methodology
Enzymes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods. / Novinec, Marko; Korenč, Matevž; Caflisch, Amedeo; Ranganathan, Rama; Lenarčič, Brigita; Baici, Antonio.

In: Nature Communications, Vol. 5, 2014, p. 3287.

Research output: Contribution to journalArticle

Novinec, Marko ; Korenč, Matevž ; Caflisch, Amedeo ; Ranganathan, Rama ; Lenarčič, Brigita ; Baici, Antonio. / A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods. In: Nature Communications. 2014 ; Vol. 5. pp. 3287.
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