The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , |
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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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) |
repository.mail.fl_str_mv |
|
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1808128789554659328 |