PLA2-like proteins myotoxic mechanism: A dynamic model description
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1038/s41598-017-15614-z http://hdl.handle.net/11449/179365 |
Resumo: | Phospholipase A2-like (PLA2-like) proteins contribute to the development of muscle necrosis in Viperidae snake bites and are not efficiently neutralized by current antivenom treatments. The toxic mechanisms of PLA2-like proteins are devoid of catalytic activity and not yet fully understood, although structural and functional experiments suggest a dimeric assembly and that the C-terminal residues are essential to myotoxicity. Herein, we characterized the functional mechanism of bothropic PLA2-like structures related to global and local measurements using the available models in the Protein Data Bank and normal mode molecular dynamics (NM-MD). Those measurements include: (i) new geometric descriptions between their monomers, based on Euler angles; (ii) characterizations of canonical and non-canonical conformations of the C-terminal residues; (iii) accessibility of the hydrophobic channel; (iv) inspection of ligands; and (v) distance of clustered residues to toxin interface of interaction. Thus, we described the allosteric activation of PLA2-like proteins and hypothesized that the natural movement between monomers, calculated from NM-MD, is related to their membrane disruption mechanism, which is important for future studies of the inhibition process. These methods and strategies can be applied to other proteins to help understand their mechanisms of action. |
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PLA2-like proteins myotoxic mechanism: A dynamic model descriptionPhospholipase A2-like (PLA2-like) proteins contribute to the development of muscle necrosis in Viperidae snake bites and are not efficiently neutralized by current antivenom treatments. The toxic mechanisms of PLA2-like proteins are devoid of catalytic activity and not yet fully understood, although structural and functional experiments suggest a dimeric assembly and that the C-terminal residues are essential to myotoxicity. Herein, we characterized the functional mechanism of bothropic PLA2-like structures related to global and local measurements using the available models in the Protein Data Bank and normal mode molecular dynamics (NM-MD). Those measurements include: (i) new geometric descriptions between their monomers, based on Euler angles; (ii) characterizations of canonical and non-canonical conformations of the C-terminal residues; (iii) accessibility of the hydrophobic channel; (iv) inspection of ligands; and (v) distance of clustered residues to toxin interface of interaction. Thus, we described the allosteric activation of PLA2-like proteins and hypothesized that the natural movement between monomers, calculated from NM-MD, is related to their membrane disruption mechanism, which is important for future studies of the inhibition process. These methods and strategies can be applied to other proteins to help understand their mechanisms of action.Departamento de Física e Biofísica Instituto de Biociências Universidade Estadual Paulista (UNESP)Departamento de Física e Biofísica Instituto de Biociências Universidade Estadual Paulista (UNESP)Universidade Estadual Paulista (Unesp)Borges, Rafael J. [UNESP]Lemke, Ney [UNESP]Fontes, Marcos R. M. [UNESP]2018-12-11T17:34:53Z2018-12-11T17:34:53Z2017-12-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://dx.doi.org/10.1038/s41598-017-15614-zScientific Reports, v. 7, n. 1, 2017.2045-2322http://hdl.handle.net/11449/17936510.1038/s41598-017-15614-z2-s2.0-850341060302-s2.0-85034106030.pdf7977035910952141Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengScientific Reports1,533info:eu-repo/semantics/openAccess2023-12-24T06:21:37Zoai:repositorio.unesp.br:11449/179365Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462023-12-24T06:21:37Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
PLA2-like proteins myotoxic mechanism: A dynamic model description |
title |
PLA2-like proteins myotoxic mechanism: A dynamic model description |
spellingShingle |
PLA2-like proteins myotoxic mechanism: A dynamic model description Borges, Rafael J. [UNESP] |
title_short |
PLA2-like proteins myotoxic mechanism: A dynamic model description |
title_full |
PLA2-like proteins myotoxic mechanism: A dynamic model description |
title_fullStr |
PLA2-like proteins myotoxic mechanism: A dynamic model description |
title_full_unstemmed |
PLA2-like proteins myotoxic mechanism: A dynamic model description |
title_sort |
PLA2-like proteins myotoxic mechanism: A dynamic model description |
author |
Borges, Rafael J. [UNESP] |
author_facet |
Borges, Rafael J. [UNESP] Lemke, Ney [UNESP] Fontes, Marcos R. M. [UNESP] |
author_role |
author |
author2 |
Lemke, Ney [UNESP] Fontes, Marcos R. M. [UNESP] |
author2_role |
author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) |
dc.contributor.author.fl_str_mv |
Borges, Rafael J. [UNESP] Lemke, Ney [UNESP] Fontes, Marcos R. M. [UNESP] |
description |
Phospholipase A2-like (PLA2-like) proteins contribute to the development of muscle necrosis in Viperidae snake bites and are not efficiently neutralized by current antivenom treatments. The toxic mechanisms of PLA2-like proteins are devoid of catalytic activity and not yet fully understood, although structural and functional experiments suggest a dimeric assembly and that the C-terminal residues are essential to myotoxicity. Herein, we characterized the functional mechanism of bothropic PLA2-like structures related to global and local measurements using the available models in the Protein Data Bank and normal mode molecular dynamics (NM-MD). Those measurements include: (i) new geometric descriptions between their monomers, based on Euler angles; (ii) characterizations of canonical and non-canonical conformations of the C-terminal residues; (iii) accessibility of the hydrophobic channel; (iv) inspection of ligands; and (v) distance of clustered residues to toxin interface of interaction. Thus, we described the allosteric activation of PLA2-like proteins and hypothesized that the natural movement between monomers, calculated from NM-MD, is related to their membrane disruption mechanism, which is important for future studies of the inhibition process. These methods and strategies can be applied to other proteins to help understand their mechanisms of action. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-12-01 2018-12-11T17:34:53Z 2018-12-11T17:34:53Z |
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/s41598-017-15614-z Scientific Reports, v. 7, n. 1, 2017. 2045-2322 http://hdl.handle.net/11449/179365 10.1038/s41598-017-15614-z 2-s2.0-85034106030 2-s2.0-85034106030.pdf 7977035910952141 |
url |
http://dx.doi.org/10.1038/s41598-017-15614-z http://hdl.handle.net/11449/179365 |
identifier_str_mv |
Scientific Reports, v. 7, n. 1, 2017. 2045-2322 10.1038/s41598-017-15614-z 2-s2.0-85034106030 2-s2.0-85034106030.pdf 7977035910952141 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Scientific Reports 1,533 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
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_ |
1799965395678920704 |