The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiae

Detalhes bibliográficos
Autor(a) principal: Pontes,Frederico J. S.
Data de Publicação: 2016
Outros Autores: Maia,Rafael T., Lima,Maria Carolina P., Ayres,Constância F.J., Soares,Thereza A.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Journal of the Brazilian Chemical Society (Online)
Texto Completo: http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532016000901602
Resumo: Glutathione S-transferases (GSTs) are enzymes capable of metabolizing cytotoxic compounds. The enzyme AgGSTE2, member of epsilon class GSTs (GSTE), is the most important GST conferring resistance to dichloro-diphenyl-trichloroethane (DDT) in Anopheles gambiae. We have investigated the conformational dynamics of three GSTE variants (GSTE2, GSTE2-I114T/F120L, GSTE5) from A. gambiae. Large-scale motions of helices H2 and H4 and conformational transition of the C-terminal governs the opening of the G-site and is expected to affect substrate binding and product release. This structural rearrangement places Glu116 (Glu120 in GSTE5) close of the thiol group of the tripeptide glutathione (GSH) cofactor, making this residue a candidate to act as a base in the activation of DDT. The structural rearrangement is noticeable for AgGSTE2-F120L, which has been shown to confer increased DDT-resistance. The other variants exhibit a more subtle rearrangement. These findings corroborate the hypothesis that the increase of the conformational dynamics of GST Epsilon class isoforms from A. gambiae promotes higher DDTase activity.
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spelling The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiaemolecular dynamics simulationevolutional constraintpositive and negative selectionmetabolic resistancemalaria vectorGlutathione S-transferases (GSTs) are enzymes capable of metabolizing cytotoxic compounds. The enzyme AgGSTE2, member of epsilon class GSTs (GSTE), is the most important GST conferring resistance to dichloro-diphenyl-trichloroethane (DDT) in Anopheles gambiae. We have investigated the conformational dynamics of three GSTE variants (GSTE2, GSTE2-I114T/F120L, GSTE5) from A. gambiae. Large-scale motions of helices H2 and H4 and conformational transition of the C-terminal governs the opening of the G-site and is expected to affect substrate binding and product release. This structural rearrangement places Glu116 (Glu120 in GSTE5) close of the thiol group of the tripeptide glutathione (GSH) cofactor, making this residue a candidate to act as a base in the activation of DDT. The structural rearrangement is noticeable for AgGSTE2-F120L, which has been shown to confer increased DDT-resistance. The other variants exhibit a more subtle rearrangement. These findings corroborate the hypothesis that the increase of the conformational dynamics of GST Epsilon class isoforms from A. gambiae promotes higher DDTase activity.Sociedade Brasileira de Química2016-09-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersiontext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532016000901602Journal of the Brazilian Chemical Society v.27 n.9 2016reponame:Journal of the Brazilian Chemical Society (Online)instname:Sociedade Brasileira de Química (SBQ)instacron:SBQ10.5935/0103-5053.20160040info:eu-repo/semantics/openAccessPontes,Frederico J. S.Maia,Rafael T.Lima,Maria Carolina P.Ayres,Constância F.J.Soares,Thereza A.eng2016-09-14T00:00:00Zoai:scielo:S0103-50532016000901602Revistahttp://jbcs.sbq.org.brONGhttps://old.scielo.br/oai/scielo-oai.php||office@jbcs.sbq.org.br1678-47900103-5053opendoar:2016-09-14T00:00Journal of the Brazilian Chemical Society (Online) - Sociedade Brasileira de Química (SBQ)false
dc.title.none.fl_str_mv The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiae
title The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiae
spellingShingle The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiae
Pontes,Frederico J. S.
molecular dynamics simulation
evolutional constraint
positive and negative selection
metabolic resistance
malaria vector
title_short The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiae
title_full The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiae
title_fullStr The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiae
title_full_unstemmed The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiae
title_sort The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiae
author Pontes,Frederico J. S.
author_facet Pontes,Frederico J. S.
Maia,Rafael T.
Lima,Maria Carolina P.
Ayres,Constância F.J.
Soares,Thereza A.
author_role author
author2 Maia,Rafael T.
Lima,Maria Carolina P.
Ayres,Constância F.J.
Soares,Thereza A.
author2_role author
author
author
author
dc.contributor.author.fl_str_mv Pontes,Frederico J. S.
Maia,Rafael T.
Lima,Maria Carolina P.
Ayres,Constância F.J.
Soares,Thereza A.
dc.subject.por.fl_str_mv molecular dynamics simulation
evolutional constraint
positive and negative selection
metabolic resistance
malaria vector
topic molecular dynamics simulation
evolutional constraint
positive and negative selection
metabolic resistance
malaria vector
description Glutathione S-transferases (GSTs) are enzymes capable of metabolizing cytotoxic compounds. The enzyme AgGSTE2, member of epsilon class GSTs (GSTE), is the most important GST conferring resistance to dichloro-diphenyl-trichloroethane (DDT) in Anopheles gambiae. We have investigated the conformational dynamics of three GSTE variants (GSTE2, GSTE2-I114T/F120L, GSTE5) from A. gambiae. Large-scale motions of helices H2 and H4 and conformational transition of the C-terminal governs the opening of the G-site and is expected to affect substrate binding and product release. This structural rearrangement places Glu116 (Glu120 in GSTE5) close of the thiol group of the tripeptide glutathione (GSH) cofactor, making this residue a candidate to act as a base in the activation of DDT. The structural rearrangement is noticeable for AgGSTE2-F120L, which has been shown to confer increased DDT-resistance. The other variants exhibit a more subtle rearrangement. These findings corroborate the hypothesis that the increase of the conformational dynamics of GST Epsilon class isoforms from A. gambiae promotes higher DDTase activity.
publishDate 2016
dc.date.none.fl_str_mv 2016-09-01
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
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dc.identifier.uri.fl_str_mv http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532016000901602
url http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532016000901602
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 10.5935/0103-5053.20160040
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv text/html
dc.publisher.none.fl_str_mv Sociedade Brasileira de Química
publisher.none.fl_str_mv Sociedade Brasileira de Química
dc.source.none.fl_str_mv Journal of the Brazilian Chemical Society v.27 n.9 2016
reponame:Journal of the Brazilian Chemical Society (Online)
instname:Sociedade Brasileira de Química (SBQ)
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instname_str Sociedade Brasileira de Química (SBQ)
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institution SBQ
reponame_str Journal of the Brazilian Chemical Society (Online)
collection Journal of the Brazilian Chemical Society (Online)
repository.name.fl_str_mv Journal of the Brazilian Chemical Society (Online) - Sociedade Brasileira de Química (SBQ)
repository.mail.fl_str_mv ||office@jbcs.sbq.org.br
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