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Mechanisms Applied by Protein Inhibitors to Inhibit Cysteine Proteases

Protein inhibitors of proteases are an important tool of nature to regulate and control proteolysis in living organisms under physiological and pathological conditions. In this review, we analyzed the mechanisms of inhibition of cysteine proteases on the basis of structural information and compiled...

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Autores principales: Tušar, Livija, Usenik, Aleksandra, Turk, Boris, Turk, Dušan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863939/
https://www.ncbi.nlm.nih.gov/pubmed/33498210
http://dx.doi.org/10.3390/ijms22030997
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author Tušar, Livija
Usenik, Aleksandra
Turk, Boris
Turk, Dušan
author_facet Tušar, Livija
Usenik, Aleksandra
Turk, Boris
Turk, Dušan
author_sort Tušar, Livija
collection PubMed
description Protein inhibitors of proteases are an important tool of nature to regulate and control proteolysis in living organisms under physiological and pathological conditions. In this review, we analyzed the mechanisms of inhibition of cysteine proteases on the basis of structural information and compiled kinetic data. The gathered structural data indicate that the protein fold is not a major obstacle for the evolution of a protease inhibitor. It appears that nature can convert almost any starting fold into an inhibitor of a protease. In addition, there appears to be no general rule governing the inhibitory mechanism. The structural data make it clear that the “lock and key” mechanism is a historical concept with limited validity. However, the analysis suggests that the shape of the active site cleft of proteases imposes some restraints. When the S1 binding site is shaped as a pocket buried in the structure of protease, inhibitors can apply substrate-like binding mechanisms. In contrast, when the S1 binding site is in part exposed to solvent, the substrate-like inhibition cannot be employed. It appears that all proteases, with the exception of papain-like proteases, belong to the first group of proteases. Finally, we show a number of examples and provide hints on how to engineer protein inhibitors.
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spelling pubmed-78639392021-02-06 Mechanisms Applied by Protein Inhibitors to Inhibit Cysteine Proteases Tušar, Livija Usenik, Aleksandra Turk, Boris Turk, Dušan Int J Mol Sci Review Protein inhibitors of proteases are an important tool of nature to regulate and control proteolysis in living organisms under physiological and pathological conditions. In this review, we analyzed the mechanisms of inhibition of cysteine proteases on the basis of structural information and compiled kinetic data. The gathered structural data indicate that the protein fold is not a major obstacle for the evolution of a protease inhibitor. It appears that nature can convert almost any starting fold into an inhibitor of a protease. In addition, there appears to be no general rule governing the inhibitory mechanism. The structural data make it clear that the “lock and key” mechanism is a historical concept with limited validity. However, the analysis suggests that the shape of the active site cleft of proteases imposes some restraints. When the S1 binding site is shaped as a pocket buried in the structure of protease, inhibitors can apply substrate-like binding mechanisms. In contrast, when the S1 binding site is in part exposed to solvent, the substrate-like inhibition cannot be employed. It appears that all proteases, with the exception of papain-like proteases, belong to the first group of proteases. Finally, we show a number of examples and provide hints on how to engineer protein inhibitors. MDPI 2021-01-20 /pmc/articles/PMC7863939/ /pubmed/33498210 http://dx.doi.org/10.3390/ijms22030997 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Tušar, Livija
Usenik, Aleksandra
Turk, Boris
Turk, Dušan
Mechanisms Applied by Protein Inhibitors to Inhibit Cysteine Proteases
title Mechanisms Applied by Protein Inhibitors to Inhibit Cysteine Proteases
title_full Mechanisms Applied by Protein Inhibitors to Inhibit Cysteine Proteases
title_fullStr Mechanisms Applied by Protein Inhibitors to Inhibit Cysteine Proteases
title_full_unstemmed Mechanisms Applied by Protein Inhibitors to Inhibit Cysteine Proteases
title_short Mechanisms Applied by Protein Inhibitors to Inhibit Cysteine Proteases
title_sort mechanisms applied by protein inhibitors to inhibit cysteine proteases
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863939/
https://www.ncbi.nlm.nih.gov/pubmed/33498210
http://dx.doi.org/10.3390/ijms22030997
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