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Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin
Tubulin is the target for many small-molecule natural compounds, which alter microtubules dynamics, and lead to cell cycle arrest and apoptosis. One of these compounds is colchicine, a plant alkaloid produced by Colchicum autumnale. While C. autumnale produces a potent cytotoxin, colchicine, and exp...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578066/ https://www.ncbi.nlm.nih.gov/pubmed/28767055 http://dx.doi.org/10.3390/ijms18081676 |
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author | Spasevska, Ivana Ayoub, Ahmed T. Winter, Philip Preto, Jordane Wong, Gane K.-S. Dumontet, Charles Tuszynski, Jack A. |
author_facet | Spasevska, Ivana Ayoub, Ahmed T. Winter, Philip Preto, Jordane Wong, Gane K.-S. Dumontet, Charles Tuszynski, Jack A. |
author_sort | Spasevska, Ivana |
collection | PubMed |
description | Tubulin is the target for many small-molecule natural compounds, which alter microtubules dynamics, and lead to cell cycle arrest and apoptosis. One of these compounds is colchicine, a plant alkaloid produced by Colchicum autumnale. While C. autumnale produces a potent cytotoxin, colchicine, and expresses its target protein, it is immune to colchicine’s cytotoxic action and the mechanism of this resistance is hitherto unknown. In the present paper, the molecular mechanisms responsible for colchicine resistance in C. autumnale are investigated and compared to human tubulin. To this end, homology models for C. autumnale α-β tubulin heterodimer are created and molecular dynamics (MD) simulations together with molecular mechanics Poisson–Boltzmann calculations (MM/PBSA) are performed to determine colchicine’s binding affinity for tubulin. Using our molecular approach, it is shown that the colchicine-binding site in C. autumnale tubulin contains a small number of amino acid substitutions compared to human tubulin. However, these substitutions induce significant reduction in the binding affinity for tubulin, and subsequently fewer conformational changes in its structure result. It is suggested that such small conformational changes are insufficient to profoundly disrupt microtubule dynamics, which explains the high resistance to colchicine by C. autumnale. |
format | Online Article Text |
id | pubmed-5578066 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-55780662017-09-05 Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin Spasevska, Ivana Ayoub, Ahmed T. Winter, Philip Preto, Jordane Wong, Gane K.-S. Dumontet, Charles Tuszynski, Jack A. Int J Mol Sci Article Tubulin is the target for many small-molecule natural compounds, which alter microtubules dynamics, and lead to cell cycle arrest and apoptosis. One of these compounds is colchicine, a plant alkaloid produced by Colchicum autumnale. While C. autumnale produces a potent cytotoxin, colchicine, and expresses its target protein, it is immune to colchicine’s cytotoxic action and the mechanism of this resistance is hitherto unknown. In the present paper, the molecular mechanisms responsible for colchicine resistance in C. autumnale are investigated and compared to human tubulin. To this end, homology models for C. autumnale α-β tubulin heterodimer are created and molecular dynamics (MD) simulations together with molecular mechanics Poisson–Boltzmann calculations (MM/PBSA) are performed to determine colchicine’s binding affinity for tubulin. Using our molecular approach, it is shown that the colchicine-binding site in C. autumnale tubulin contains a small number of amino acid substitutions compared to human tubulin. However, these substitutions induce significant reduction in the binding affinity for tubulin, and subsequently fewer conformational changes in its structure result. It is suggested that such small conformational changes are insufficient to profoundly disrupt microtubule dynamics, which explains the high resistance to colchicine by C. autumnale. MDPI 2017-08-02 /pmc/articles/PMC5578066/ /pubmed/28767055 http://dx.doi.org/10.3390/ijms18081676 Text en © 2017 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 | Article Spasevska, Ivana Ayoub, Ahmed T. Winter, Philip Preto, Jordane Wong, Gane K.-S. Dumontet, Charles Tuszynski, Jack A. Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin |
title | Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin |
title_full | Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin |
title_fullStr | Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin |
title_full_unstemmed | Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin |
title_short | Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin |
title_sort | modeling the colchicum autumnale tubulin and a comparison of its interaction with colchicine to human tubulin |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578066/ https://www.ncbi.nlm.nih.gov/pubmed/28767055 http://dx.doi.org/10.3390/ijms18081676 |
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