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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-7863939 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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