The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description

Detalhes bibliográficos
Autor(a) principal: Gomes, Antoniel A. S. [UNESP]
Data de Publicação: 2020
Outros Autores: Cardoso, Fabio F. [UNESP], Souza, Maximilia F., Oliveira, Cristiano L. P., Perahia, David, Magro, Angelo J. [UNESP], Fontes, Marcos R. M. [UNESP]
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.1038/s41598-020-73134-9
http://hdl.handle.net/11449/205238
Resumo: The activation process of phospholipase A2-like (PLA2-like) toxins is a key step in their molecular mechanism, which involves oligomeric changes leading to the exposure of specific sites. Few studies have focused on the characterization of allosteric activators and the features that distinguish them from inhibitors. Herein, a comprehensive study with the BthTX-I toxin from Bothrops jararacussu venom bound or unbound to α-tocopherol (αT) was carried out. The oligomerization state of BthTX-I bound or unbound to αT in solution was studied and indicated that the toxin is predominantly monomeric but tends to oligomerize when complexed with αT. In silico molecular simulations showed the toxin presents higher conformational changes in the absence of αT,which suggests that it is important to stabilize the structure of the toxin. The transition between the two states (active/inactive) was also studied, showing that only the unbound BthTX-I system could migrate to the inactive state. In contrast, the presence of αT induces the toxin to leave the inactive state, guiding it towards the active state, with more regions exposed to the solvent, particularly its active site. Finally, the structural determinants necessary for a molecule to be an inhibitor or activator were analyzed in light of the obtained results.
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spelling The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic descriptionThe activation process of phospholipase A2-like (PLA2-like) toxins is a key step in their molecular mechanism, which involves oligomeric changes leading to the exposure of specific sites. Few studies have focused on the characterization of allosteric activators and the features that distinguish them from inhibitors. Herein, a comprehensive study with the BthTX-I toxin from Bothrops jararacussu venom bound or unbound to α-tocopherol (αT) was carried out. The oligomerization state of BthTX-I bound or unbound to αT in solution was studied and indicated that the toxin is predominantly monomeric but tends to oligomerize when complexed with αT. In silico molecular simulations showed the toxin presents higher conformational changes in the absence of αT,which suggests that it is important to stabilize the structure of the toxin. The transition between the two states (active/inactive) was also studied, showing that only the unbound BthTX-I system could migrate to the inactive state. In contrast, the presence of αT induces the toxin to leave the inactive state, guiding it towards the active state, with more regions exposed to the solvent, particularly its active site. Finally, the structural determinants necessary for a molecule to be an inhibitor or activator were analyzed in light of the obtained results.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Departamento de Biofísica e Farmacologia Instituto de Biociências Universidade Estadual Paulista (UNESP)Laboratoire de Biologie et de Pharmacologie Appliquée École Normale Supérieure Paris Saclay UMR 8113 CNRS, 4 Avenue des SciencesDepartamento de Física Experimental Instituto de Física Universidade de São Paulo (USP)Departamento de Biotecnologia e Bioprocessos Faculdade de Ciências Agronômicas Universidade Estadual Paulista (UNESP)Instituto de Biotecnologia Universidade Estadual Paulista (UNESP)Departamento de Biofísica e Farmacologia Instituto de Biociências Universidade Estadual Paulista (UNESP)Departamento de Biotecnologia e Bioprocessos Faculdade de Ciências Agronômicas Universidade Estadual Paulista (UNESP)Instituto de Biotecnologia Universidade Estadual Paulista (UNESP)CNPq: 302883/2017-7CNPq: 401190/2017-0CAPES: 88881.134154/2016-01CAPES: 88882.183567/2007-01Universidade Estadual Paulista (Unesp)CNRSUniversidade de São Paulo (USP)Gomes, Antoniel A. S. [UNESP]Cardoso, Fabio F. [UNESP]Souza, Maximilia F.Oliveira, Cristiano L. P.Perahia, DavidMagro, Angelo J. [UNESP]Fontes, Marcos R. M. [UNESP]2021-06-25T10:12:08Z2021-06-25T10:12:08Z2020-12-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41598-020-73134-9Scientific Reports, v. 10, n. 1, 2020.2045-2322http://hdl.handle.net/11449/20523810.1038/s41598-020-73134-92-s2.0-85091788159Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengScientific Reportsinfo:eu-repo/semantics/openAccess2021-10-23T12:19:10Zoai:repositorio.unesp.br:11449/205238Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T17:18:53.240734Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description
title The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description
spellingShingle The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description
Gomes, Antoniel A. S. [UNESP]
title_short The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description
title_full The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description
title_fullStr The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description
title_full_unstemmed The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description
title_sort The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description
author Gomes, Antoniel A. S. [UNESP]
author_facet Gomes, Antoniel A. S. [UNESP]
Cardoso, Fabio F. [UNESP]
Souza, Maximilia F.
Oliveira, Cristiano L. P.
Perahia, David
Magro, Angelo J. [UNESP]
Fontes, Marcos R. M. [UNESP]
author_role author
author2 Cardoso, Fabio F. [UNESP]
Souza, Maximilia F.
Oliveira, Cristiano L. P.
Perahia, David
Magro, Angelo J. [UNESP]
Fontes, Marcos R. M. [UNESP]
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade Estadual Paulista (Unesp)
CNRS
Universidade de São Paulo (USP)
dc.contributor.author.fl_str_mv Gomes, Antoniel A. S. [UNESP]
Cardoso, Fabio F. [UNESP]
Souza, Maximilia F.
Oliveira, Cristiano L. P.
Perahia, David
Magro, Angelo J. [UNESP]
Fontes, Marcos R. M. [UNESP]
description The activation process of phospholipase A2-like (PLA2-like) toxins is a key step in their molecular mechanism, which involves oligomeric changes leading to the exposure of specific sites. Few studies have focused on the characterization of allosteric activators and the features that distinguish them from inhibitors. Herein, a comprehensive study with the BthTX-I toxin from Bothrops jararacussu venom bound or unbound to α-tocopherol (αT) was carried out. The oligomerization state of BthTX-I bound or unbound to αT in solution was studied and indicated that the toxin is predominantly monomeric but tends to oligomerize when complexed with αT. In silico molecular simulations showed the toxin presents higher conformational changes in the absence of αT,which suggests that it is important to stabilize the structure of the toxin. The transition between the two states (active/inactive) was also studied, showing that only the unbound BthTX-I system could migrate to the inactive state. In contrast, the presence of αT induces the toxin to leave the inactive state, guiding it towards the active state, with more regions exposed to the solvent, particularly its active site. Finally, the structural determinants necessary for a molecule to be an inhibitor or activator were analyzed in light of the obtained results.
publishDate 2020
dc.date.none.fl_str_mv 2020-12-01
2021-06-25T10:12:08Z
2021-06-25T10:12:08Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.1038/s41598-020-73134-9
Scientific Reports, v. 10, n. 1, 2020.
2045-2322
http://hdl.handle.net/11449/205238
10.1038/s41598-020-73134-9
2-s2.0-85091788159
url http://dx.doi.org/10.1038/s41598-020-73134-9
http://hdl.handle.net/11449/205238
identifier_str_mv Scientific Reports, v. 10, n. 1, 2020.
2045-2322
10.1038/s41598-020-73134-9
2-s2.0-85091788159
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Scientific Reports
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv Scopus
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
instacron:UNESP
instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
collection Repositório Institucional da UNESP
repository.name.fl_str_mv Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)
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