The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance in Anopheles gambiae
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , |
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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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 |
format |
article |
status_str |
publishedVersion |
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) instacron:SBQ |
instname_str |
Sociedade Brasileira de Química (SBQ) |
instacron_str |
SBQ |
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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1750318178720808960 |