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Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding

[Image: see text] The interactions between proteins and ligands are involved in various biological functions. While experimental structures provide key static structural information of ligand-unbound and ligand-bound proteins, dynamic information is often insufficient for understanding the detailed...

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Autores principales: Hirano, Yoshinori, Okimoto, Noriaki, Fujita, Shigeo, Taiji, Makoto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280666/
https://www.ncbi.nlm.nih.gov/pubmed/34278146
http://dx.doi.org/10.1021/acsomega.1c02159
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author Hirano, Yoshinori
Okimoto, Noriaki
Fujita, Shigeo
Taiji, Makoto
author_facet Hirano, Yoshinori
Okimoto, Noriaki
Fujita, Shigeo
Taiji, Makoto
author_sort Hirano, Yoshinori
collection PubMed
description [Image: see text] The interactions between proteins and ligands are involved in various biological functions. While experimental structures provide key static structural information of ligand-unbound and ligand-bound proteins, dynamic information is often insufficient for understanding the detailed mechanism of protein–ligand binding. Here, we studied the conformational changes of the tankyrase 2 binding pocket upon ligand binding using molecular dynamics simulations of the ligand-unbound and ligand-bound proteins. The ligand-binding pocket has two subsites: the nicotinamide and adenosine subsite. Comparative analysis of these molecular dynamics trajectories revealed that the conformational change of the ligand-binding pocket was characterized by four distinct conformations of the ligand-binding pocket. Two of the four conformations were observed only in molecular dynamics simulations. We found that the pocket conformational change on ligand binding was based on the connection between the nicotinamide and adenosine subsites that are located adjacently in the pocket. From the analysis, we proposed the protein–ligand binding mechanism of tankyrase 2. Finally, we discussed the computational prediction of the ligand binding pose using the tankyrase 2 structures obtained from the molecular dynamics simulations.
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spelling pubmed-82806662021-07-16 Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding Hirano, Yoshinori Okimoto, Noriaki Fujita, Shigeo Taiji, Makoto ACS Omega [Image: see text] The interactions between proteins and ligands are involved in various biological functions. While experimental structures provide key static structural information of ligand-unbound and ligand-bound proteins, dynamic information is often insufficient for understanding the detailed mechanism of protein–ligand binding. Here, we studied the conformational changes of the tankyrase 2 binding pocket upon ligand binding using molecular dynamics simulations of the ligand-unbound and ligand-bound proteins. The ligand-binding pocket has two subsites: the nicotinamide and adenosine subsite. Comparative analysis of these molecular dynamics trajectories revealed that the conformational change of the ligand-binding pocket was characterized by four distinct conformations of the ligand-binding pocket. Two of the four conformations were observed only in molecular dynamics simulations. We found that the pocket conformational change on ligand binding was based on the connection between the nicotinamide and adenosine subsites that are located adjacently in the pocket. From the analysis, we proposed the protein–ligand binding mechanism of tankyrase 2. Finally, we discussed the computational prediction of the ligand binding pose using the tankyrase 2 structures obtained from the molecular dynamics simulations. American Chemical Society 2021-06-29 /pmc/articles/PMC8280666/ /pubmed/34278146 http://dx.doi.org/10.1021/acsomega.1c02159 Text en © 2021 The Authors. Published by American Chemical Society Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Hirano, Yoshinori
Okimoto, Noriaki
Fujita, Shigeo
Taiji, Makoto
Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding
title Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding
title_full Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding
title_fullStr Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding
title_full_unstemmed Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding
title_short Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding
title_sort molecular dynamics study of conformational changes of tankyrase 2 binding subsites upon ligand binding
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280666/
https://www.ncbi.nlm.nih.gov/pubmed/34278146
http://dx.doi.org/10.1021/acsomega.1c02159
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