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pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis

Cathepsin D (CatD; EC 3.4.23.5) family peptidases of parasitic organisms are regarded as potential drug targets as they play critical roles in the physiology and pathobiology of parasites. Previously, we characterized the biochemical features of cathepsin D isozyme 2 (CatD2) in the carcinogenic live...

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Autores principales: Kang, Jung-Mi, Lê, Hương Giang, Na, Byoung-Kuk, Yoo, Won Gi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466142/
https://www.ncbi.nlm.nih.gov/pubmed/34578162
http://dx.doi.org/10.3390/pathogens10091128
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author Kang, Jung-Mi
Lê, Hương Giang
Na, Byoung-Kuk
Yoo, Won Gi
author_facet Kang, Jung-Mi
Lê, Hương Giang
Na, Byoung-Kuk
Yoo, Won Gi
author_sort Kang, Jung-Mi
collection PubMed
description Cathepsin D (CatD; EC 3.4.23.5) family peptidases of parasitic organisms are regarded as potential drug targets as they play critical roles in the physiology and pathobiology of parasites. Previously, we characterized the biochemical features of cathepsin D isozyme 2 (CatD2) in the carcinogenic liver fluke Clonorchis sinensis (CsCatD2). In this study, we performed all-atomic molecular dynamics simulations by applying different systems for the ligand-free/bound forms under neutral and acidic conditions to investigate the pH-dependent structural alterations and associated functional changes in CsCatD2. CsCatD2 showed several distinctive characteristics as follows: (1) acidic pH caused major conformational transitions from open to closed state in this enzyme; (2) during 30–36-ns simulations, acidic pH contributed significantly to the formation of rigid β-sheets around the catalytic residue Asp(219), higher occupancy (0% to 99%) of hydrogen bond than that of Asp(33), and enhanced stabilization of the CsCatD2-inhibtor complex; (3) neutral pH-induced displacement of the N-terminal part to hinder the accessibility of the active site and open allosteric site of this enzyme; and (4) the flap dynamics metrics, including distance (d(1)), TriCα angles (θ(1) and θ(2)), and dihedral angle (ϕ), account for the asymmetrical twisting motion of the active site of this enzyme. These findings provide an in-depth understanding of the pH-dependent structural dynamics of free and bound forms of CsCatD2 and basic information for the rational design of an inhibitor as a drug targeting parasitic CatD.
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spelling pubmed-84661422021-09-27 pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis Kang, Jung-Mi Lê, Hương Giang Na, Byoung-Kuk Yoo, Won Gi Pathogens Article Cathepsin D (CatD; EC 3.4.23.5) family peptidases of parasitic organisms are regarded as potential drug targets as they play critical roles in the physiology and pathobiology of parasites. Previously, we characterized the biochemical features of cathepsin D isozyme 2 (CatD2) in the carcinogenic liver fluke Clonorchis sinensis (CsCatD2). In this study, we performed all-atomic molecular dynamics simulations by applying different systems for the ligand-free/bound forms under neutral and acidic conditions to investigate the pH-dependent structural alterations and associated functional changes in CsCatD2. CsCatD2 showed several distinctive characteristics as follows: (1) acidic pH caused major conformational transitions from open to closed state in this enzyme; (2) during 30–36-ns simulations, acidic pH contributed significantly to the formation of rigid β-sheets around the catalytic residue Asp(219), higher occupancy (0% to 99%) of hydrogen bond than that of Asp(33), and enhanced stabilization of the CsCatD2-inhibtor complex; (3) neutral pH-induced displacement of the N-terminal part to hinder the accessibility of the active site and open allosteric site of this enzyme; and (4) the flap dynamics metrics, including distance (d(1)), TriCα angles (θ(1) and θ(2)), and dihedral angle (ϕ), account for the asymmetrical twisting motion of the active site of this enzyme. These findings provide an in-depth understanding of the pH-dependent structural dynamics of free and bound forms of CsCatD2 and basic information for the rational design of an inhibitor as a drug targeting parasitic CatD. MDPI 2021-09-02 /pmc/articles/PMC8466142/ /pubmed/34578162 http://dx.doi.org/10.3390/pathogens10091128 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kang, Jung-Mi
Lê, Hương Giang
Na, Byoung-Kuk
Yoo, Won Gi
pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis
title pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis
title_full pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis
title_fullStr pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis
title_full_unstemmed pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis
title_short pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis
title_sort ph-dependent structural dynamics of cathepsin d-family aspartic peptidase of clonorchis sinensis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466142/
https://www.ncbi.nlm.nih.gov/pubmed/34578162
http://dx.doi.org/10.3390/pathogens10091128
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