In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.biochi.2020.12.008 http://hdl.handle.net/11449/205625 |
Resumo: | Snakebite envenomation has been categorized by World Health Organization as a category A neglected tropical disease, since it causes chronic psychological disorders, physical disablement and death. Ophidian accidents may cause local myonecrosis that cause drastic sequelae, which are not efficiently neutralized via serum therapy. Phospholipase A2-like (PLA2-like) myotoxins have a major role in the local effects caused by several snake venoms. We previously demonstrated that chicoric acid (CA) is an efficient inhibitor of the BthTX-I myotoxin and solved the X-ray structure of complex. Herein, we assess the oligomeric behavior of the BthTX-I/CA complex in solution under different physical-chemical conditions and using toxin obtained by two different biochemical methodologies to fully elucidate structural bases of inhibition of myotoxins by CA. We demonstrated the ability of PLA2-like proteins to form different oligomeric assemblies in the presence of certain inhibitors, which can also be modulated by buffer polarity change. In the presence of ethanol, BthTX-I/CA remains predominantly in a monomeric conformation, which prevents it from being in its active form (dimeric conformation). In contrast, in the absence of ethanol, the tetramer assembly was observed, which hid key regions of the protein responsible for docking and disruption of the muscle membrane. Therefore, the “plasticity” of these proteins with regard to their abilities to form oligomeric assemblies is a key issue for the future development of therapeutic agents to complement of serum therapy. |
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In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibitionMyotoxicity inhibitionOligomerizationPhospholipase A2-like myotoxinsPlant compoundSnake venomSnakebite envenomation has been categorized by World Health Organization as a category A neglected tropical disease, since it causes chronic psychological disorders, physical disablement and death. Ophidian accidents may cause local myonecrosis that cause drastic sequelae, which are not efficiently neutralized via serum therapy. Phospholipase A2-like (PLA2-like) myotoxins have a major role in the local effects caused by several snake venoms. We previously demonstrated that chicoric acid (CA) is an efficient inhibitor of the BthTX-I myotoxin and solved the X-ray structure of complex. Herein, we assess the oligomeric behavior of the BthTX-I/CA complex in solution under different physical-chemical conditions and using toxin obtained by two different biochemical methodologies to fully elucidate structural bases of inhibition of myotoxins by CA. We demonstrated the ability of PLA2-like proteins to form different oligomeric assemblies in the presence of certain inhibitors, which can also be modulated by buffer polarity change. In the presence of ethanol, BthTX-I/CA remains predominantly in a monomeric conformation, which prevents it from being in its active form (dimeric conformation). In contrast, in the absence of ethanol, the tetramer assembly was observed, which hid key regions of the protein responsible for docking and disruption of the muscle membrane. Therefore, the “plasticity” of these proteins with regard to their abilities to form oligomeric assemblies is a key issue for the future development of therapeutic agents to complement of serum therapy.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Departamento de Biofísica e Farmacologia Instituto de Biociências Universidade Estadual Paulista (UNESP)Instituto de Física Universidade de São Paulo (USP)Departamento de Biofísica e Farmacologia Instituto de Biociências Universidade Estadual Paulista (UNESP)Universidade Estadual Paulista (Unesp)Universidade de São Paulo (USP)Cardoso, Fábio F. [UNESP]de Souza, Maximilia F.Oliveira, Cristiano L.P.Fontes, Marcos R.M. [UNESP]2021-06-25T10:18:30Z2021-06-25T10:18:30Z2021-02-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article145-153http://dx.doi.org/10.1016/j.biochi.2020.12.008Biochimie, v. 181, p. 145-153.6183-16380300-9084http://hdl.handle.net/11449/20562510.1016/j.biochi.2020.12.0082-s2.0-85098053281Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBiochimieinfo:eu-repo/semantics/openAccess2021-10-22T12:24:53Zoai:repositorio.unesp.br:11449/205625Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T20:44:19.744307Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition |
title |
In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition |
spellingShingle |
In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition Cardoso, Fábio F. [UNESP] Myotoxicity inhibition Oligomerization Phospholipase A2-like myotoxins Plant compound Snake venom |
title_short |
In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition |
title_full |
In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition |
title_fullStr |
In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition |
title_full_unstemmed |
In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition |
title_sort |
In-solution structural studies involving a phospholipase A2-like myotoxin and a natural inhibitor: Plasticity of oligomeric assembly affects mechanisms of inhibition |
author |
Cardoso, Fábio F. [UNESP] |
author_facet |
Cardoso, Fábio F. [UNESP] de Souza, Maximilia F. Oliveira, Cristiano L.P. Fontes, Marcos R.M. [UNESP] |
author_role |
author |
author2 |
de Souza, Maximilia F. Oliveira, Cristiano L.P. Fontes, Marcos R.M. [UNESP] |
author2_role |
author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) Universidade de São Paulo (USP) |
dc.contributor.author.fl_str_mv |
Cardoso, Fábio F. [UNESP] de Souza, Maximilia F. Oliveira, Cristiano L.P. Fontes, Marcos R.M. [UNESP] |
dc.subject.por.fl_str_mv |
Myotoxicity inhibition Oligomerization Phospholipase A2-like myotoxins Plant compound Snake venom |
topic |
Myotoxicity inhibition Oligomerization Phospholipase A2-like myotoxins Plant compound Snake venom |
description |
Snakebite envenomation has been categorized by World Health Organization as a category A neglected tropical disease, since it causes chronic psychological disorders, physical disablement and death. Ophidian accidents may cause local myonecrosis that cause drastic sequelae, which are not efficiently neutralized via serum therapy. Phospholipase A2-like (PLA2-like) myotoxins have a major role in the local effects caused by several snake venoms. We previously demonstrated that chicoric acid (CA) is an efficient inhibitor of the BthTX-I myotoxin and solved the X-ray structure of complex. Herein, we assess the oligomeric behavior of the BthTX-I/CA complex in solution under different physical-chemical conditions and using toxin obtained by two different biochemical methodologies to fully elucidate structural bases of inhibition of myotoxins by CA. We demonstrated the ability of PLA2-like proteins to form different oligomeric assemblies in the presence of certain inhibitors, which can also be modulated by buffer polarity change. In the presence of ethanol, BthTX-I/CA remains predominantly in a monomeric conformation, which prevents it from being in its active form (dimeric conformation). In contrast, in the absence of ethanol, the tetramer assembly was observed, which hid key regions of the protein responsible for docking and disruption of the muscle membrane. Therefore, the “plasticity” of these proteins with regard to their abilities to form oligomeric assemblies is a key issue for the future development of therapeutic agents to complement of serum therapy. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-06-25T10:18:30Z 2021-06-25T10:18:30Z 2021-02-01 |
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/10.1016/j.biochi.2020.12.008 Biochimie, v. 181, p. 145-153. 6183-1638 0300-9084 http://hdl.handle.net/11449/205625 10.1016/j.biochi.2020.12.008 2-s2.0-85098053281 |
url |
http://dx.doi.org/10.1016/j.biochi.2020.12.008 http://hdl.handle.net/11449/205625 |
identifier_str_mv |
Biochimie, v. 181, p. 145-153. 6183-1638 0300-9084 10.1016/j.biochi.2020.12.008 2-s2.0-85098053281 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Biochimie |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
145-153 |
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 |
|
_version_ |
1808129240493719552 |