Probing the activity modification space of the cysteine peptidase cathepsin K with novel allosteric modifiers.

Targeting allosteric sites is gaining increasing recognition as a strategy for modulating the activity of enzymes, especially in drug design. Here we investigate the mechanisms of allosteric regulation of cathepsin K as a representative of cysteine cathepsins and a promising drug target for the trea...

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Autores principales:	Marko Novinec, Brigita Lenarčič, Antonio Baici
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/912fa9a5bec241118d3fe8c7193ca859
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spelling	oai:doaj.org-article:912fa9a5bec241118d3fe8c7193ca8592021-11-25T06:02:08ZProbing the activity modification space of the cysteine peptidase cathepsin K with novel allosteric modifiers.1932-620310.1371/journal.pone.0106642https://doaj.org/article/912fa9a5bec241118d3fe8c7193ca8592014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25184245/?tool=EBIhttps://doaj.org/toc/1932-6203Targeting allosteric sites is gaining increasing recognition as a strategy for modulating the activity of enzymes, especially in drug design. Here we investigate the mechanisms of allosteric regulation of cathepsin K as a representative of cysteine cathepsins and a promising drug target for the treatment of osteoporosis. Eight novel modifiers are identified by computational targeting of predicted allosteric sites on the surface of the enzyme. All act via hyperbolic kinetic mechanisms in presence of low molecular mass substrates, as expected for allosteric effectors. Two compounds have sizable effects on enzyme activity using interstitial collagen as a natural substrate of cathepsin K and four compounds show a significantly stabilizing effect on cathepsin K. The concept of activity modification space is introduced to obtain a global perspective of the effects elicited by the modifiers. Analysis of the activity modification space reveals that the activity of cathepsin K is regulated via multiple, different allosteric mechanisms.Marko NovinecBrigita LenarčičAntonio BaiciPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 9, p e106642 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marko Novinec Brigita Lenarčič Antonio Baici Probing the activity modification space of the cysteine peptidase cathepsin K with novel allosteric modifiers.
description	Targeting allosteric sites is gaining increasing recognition as a strategy for modulating the activity of enzymes, especially in drug design. Here we investigate the mechanisms of allosteric regulation of cathepsin K as a representative of cysteine cathepsins and a promising drug target for the treatment of osteoporosis. Eight novel modifiers are identified by computational targeting of predicted allosteric sites on the surface of the enzyme. All act via hyperbolic kinetic mechanisms in presence of low molecular mass substrates, as expected for allosteric effectors. Two compounds have sizable effects on enzyme activity using interstitial collagen as a natural substrate of cathepsin K and four compounds show a significantly stabilizing effect on cathepsin K. The concept of activity modification space is introduced to obtain a global perspective of the effects elicited by the modifiers. Analysis of the activity modification space reveals that the activity of cathepsin K is regulated via multiple, different allosteric mechanisms.
format	article
author	Marko Novinec Brigita Lenarčič Antonio Baici
author_facet	Marko Novinec Brigita Lenarčič Antonio Baici
author_sort	Marko Novinec
title	Probing the activity modification space of the cysteine peptidase cathepsin K with novel allosteric modifiers.
title_short	Probing the activity modification space of the cysteine peptidase cathepsin K with novel allosteric modifiers.
title_full	Probing the activity modification space of the cysteine peptidase cathepsin K with novel allosteric modifiers.
title_fullStr	Probing the activity modification space of the cysteine peptidase cathepsin K with novel allosteric modifiers.
title_full_unstemmed	Probing the activity modification space of the cysteine peptidase cathepsin K with novel allosteric modifiers.
title_sort	probing the activity modification space of the cysteine peptidase cathepsin k with novel allosteric modifiers.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/912fa9a5bec241118d3fe8c7193ca859
work_keys_str_mv	AT markonovinec probingtheactivitymodificationspaceofthecysteinepeptidasecathepsinkwithnovelallostericmodifiers AT brigitalenarcic probingtheactivitymodificationspaceofthecysteinepeptidasecathepsinkwithnovelallostericmodifiers AT antoniobaici probingtheactivitymodificationspaceofthecysteinepeptidasecathepsinkwithnovelallostericmodifiers
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Probing the activity modification space of the cysteine peptidase cathepsin K with novel allosteric modifiers.

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