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Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvβ3 Integrin: In-Silico Based Study

BACKGROUND: Thyroid hormones (TH), T4 and T3, mediate pro-mitogenic effects in cancer cells through binding the membrane receptor αvβ3 integrin. The deaminated analogue tetrac effectively blocks TH binding to this receptor and prevents their action. While computational data on TH binding to the αvβ3...

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Autores principales: Tobi, Dror, Krashin, Eilon, Davis, Paul J., Cody, Vivian, Ellis, Martin, Ashur-Fabian, Osnat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9186291/
https://www.ncbi.nlm.nih.gov/pubmed/35692387
http://dx.doi.org/10.3389/fendo.2022.895240
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author Tobi, Dror
Krashin, Eilon
Davis, Paul J.
Cody, Vivian
Ellis, Martin
Ashur-Fabian, Osnat
author_facet Tobi, Dror
Krashin, Eilon
Davis, Paul J.
Cody, Vivian
Ellis, Martin
Ashur-Fabian, Osnat
author_sort Tobi, Dror
collection PubMed
description BACKGROUND: Thyroid hormones (TH), T4 and T3, mediate pro-mitogenic effects in cancer cells through binding the membrane receptor αvβ3 integrin. The deaminated analogue tetrac effectively blocks TH binding to this receptor and prevents their action. While computational data on TH binding to the αvβ3 integrin was published, a comprehensive analysis of additional TH metabolites is lacking. METHODS: In-silico docking of 26 TH metabolites, including the biologically active thyroid hormones (T3 and T4) and an array of sulfated, deiodinated, deaminated or decarboxylated metabolites, to the αvβ3 receptor binding pocket was performed using DOCK6, based on the three-dimensional representation of the crystallographic structure of the integrin. As the TH binding site upon the integrin is at close proximity to the well-defined RGD binding site, linear and cyclic RGD were included as a reference. Binding energy was calculated for each receptor-ligand complex using Grid score and Amber score with distance movable region protocol. RESULTS: All TH molecules demonstrated negative free energy, suggesting affinity to the αvβ3 integrin. Notably, based on both Grid and Amber scores sulfated forms of 3,3’ T2 (3,3’ T2S) and T4 (T4S) demonstrated the highest binding affinity to the integrin, compared to both cyclic RGD and an array of examined TH metabolites. The major thyroid hormones, T3 and T4, showed high affinity to the integrin, which was superior to that of linear RGD. For all hormone metabolites, decarboxylation led to decreased affinity. This corresponds with the observation that the carboxylic group mediates binding to the integrin pocket via divalent cations at the metal-ion-dependent adhesion (MIDAS) motif site. A similar reduced affinity was documented for deaminated forms of T3 (triac) and T4 (tetrac). Lastly, the reverse forms of T3, T3S, and T3AM showed higher Amber scores relative to their native form, indicating that iodination at position 5 is associated with increased binding affinity compared to position 5’. SUMMARY: Three-dimensional docking of various TH metabolites uncovered a structural basis for a differential computational free energy to the αvβ3 integrin. These findings may suggest that naturally occurring endogenous TH metabolites may impact integrin-mediate intracellular pathways in physiology and cancer.
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spelling pubmed-91862912022-06-11 Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvβ3 Integrin: In-Silico Based Study Tobi, Dror Krashin, Eilon Davis, Paul J. Cody, Vivian Ellis, Martin Ashur-Fabian, Osnat Front Endocrinol (Lausanne) Endocrinology BACKGROUND: Thyroid hormones (TH), T4 and T3, mediate pro-mitogenic effects in cancer cells through binding the membrane receptor αvβ3 integrin. The deaminated analogue tetrac effectively blocks TH binding to this receptor and prevents their action. While computational data on TH binding to the αvβ3 integrin was published, a comprehensive analysis of additional TH metabolites is lacking. METHODS: In-silico docking of 26 TH metabolites, including the biologically active thyroid hormones (T3 and T4) and an array of sulfated, deiodinated, deaminated or decarboxylated metabolites, to the αvβ3 receptor binding pocket was performed using DOCK6, based on the three-dimensional representation of the crystallographic structure of the integrin. As the TH binding site upon the integrin is at close proximity to the well-defined RGD binding site, linear and cyclic RGD were included as a reference. Binding energy was calculated for each receptor-ligand complex using Grid score and Amber score with distance movable region protocol. RESULTS: All TH molecules demonstrated negative free energy, suggesting affinity to the αvβ3 integrin. Notably, based on both Grid and Amber scores sulfated forms of 3,3’ T2 (3,3’ T2S) and T4 (T4S) demonstrated the highest binding affinity to the integrin, compared to both cyclic RGD and an array of examined TH metabolites. The major thyroid hormones, T3 and T4, showed high affinity to the integrin, which was superior to that of linear RGD. For all hormone metabolites, decarboxylation led to decreased affinity. This corresponds with the observation that the carboxylic group mediates binding to the integrin pocket via divalent cations at the metal-ion-dependent adhesion (MIDAS) motif site. A similar reduced affinity was documented for deaminated forms of T3 (triac) and T4 (tetrac). Lastly, the reverse forms of T3, T3S, and T3AM showed higher Amber scores relative to their native form, indicating that iodination at position 5 is associated with increased binding affinity compared to position 5’. SUMMARY: Three-dimensional docking of various TH metabolites uncovered a structural basis for a differential computational free energy to the αvβ3 integrin. These findings may suggest that naturally occurring endogenous TH metabolites may impact integrin-mediate intracellular pathways in physiology and cancer. Frontiers Media S.A. 2022-05-27 /pmc/articles/PMC9186291/ /pubmed/35692387 http://dx.doi.org/10.3389/fendo.2022.895240 Text en Copyright © 2022 Tobi, Krashin, Davis, Cody, Ellis and Ashur-Fabian https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Tobi, Dror
Krashin, Eilon
Davis, Paul J.
Cody, Vivian
Ellis, Martin
Ashur-Fabian, Osnat
Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvβ3 Integrin: In-Silico Based Study
title Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvβ3 Integrin: In-Silico Based Study
title_full Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvβ3 Integrin: In-Silico Based Study
title_fullStr Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvβ3 Integrin: In-Silico Based Study
title_full_unstemmed Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvβ3 Integrin: In-Silico Based Study
title_short Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvβ3 Integrin: In-Silico Based Study
title_sort three-dimensional modeling of thyroid hormone metabolites binding to the cancer-relevant αvβ3 integrin: in-silico based study
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9186291/
https://www.ncbi.nlm.nih.gov/pubmed/35692387
http://dx.doi.org/10.3389/fendo.2022.895240
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