Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors

Detalhes bibliográficos
Autor(a) principal: Machado, Lucas de Almeida
Data de Publicação: 2020
Outros Autores: Guimarães, Ana Carolina Ramos
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/45910
Resumo: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.
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spelling Machado, Lucas de AlmeidaGuimarães, Ana Carolina Ramos2021-02-01T19:35:46Z2021-02-01T19:35:46Z2020MACHADO, Lucas de Almeida; GUIMARÃES, Ana Carolina. Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors, v. 7, Article 170, 10p, Aug. 2020.2296-889Xhttps://www.arca.fiocruz.br/handle/icict/4591010.3389/fmolb.2020.00170engFrontiers MediaHIV-1ResistênciaInibidores de IntegraseIntasomeDinâmica molecularHIV-1integraseIntasomeResistanceMolecular dynamicsInibidores de IntegraseEvidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitorsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.HIV-1 integrase is the enzyme responsible for integrating the viral DNA into the host genome and is one of the main targets for antiretroviral therapy; however, there are documented cases of resistance against all the currently used integrase strand transfer inhibitors (INSTIs). While some resistance-related mutations occur near the inhibitor’s binding site, the mutation N155H occurs on the opposite side of the drug-interacting Mg2C ions, thus, not interacting directly with the drug molecules and currently lacking an explanation for its resistance mechanism. Moreover, mutation N155H and the resistance-related mutation Q148H are mutually exclusive for unknown reasons. In the present study, we use molecular dynamics simulations to understand the impact of the N155H mutation in the HIV-1 integrase structure and dynamics, when alone or in combination with Q148H. Our findings suggest that the Mg2C ions of the active site adopt different orientations in each of the mutants, causing the catalytic triad residues involved in the ion coordination to adapt their side-chain configurations, completely changing the INSTIs binding site. The change in the ion coordination also seems to affect the flexibility of the terminal viral DNA nucleotide near the active site, potentially impairing the induced-fit mechanism of the drugs. The explanations obtained from our simulations corroborate previous hypotheses drawn from crystallographic studies. The proposed resistance mechanism can also explain the resistance caused by other mutations that take place in the same region of the integrase and help uncover the structural details of other HIV-1 resistance mechanisms.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/45910/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALLucasMachado_AnaCarolinaGUmaraes_IOC_2020.pdfLucasMachado_AnaCarolinaGUmaraes_IOC_2020.pdfapplication/pdf7029142https://www.arca.fiocruz.br/bitstream/icict/45910/2/LucasMachado_AnaCarolinaGUmaraes_IOC_2020.pdf7fc80174791a633a667003ac8e168de5MD52TEXTLucasMachado_AnaCarolinaGUmaraes_IOC_2020.pdf.txtLucasMachado_AnaCarolinaGUmaraes_IOC_2020.pdf.txtExtracted 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dc.title.pt_BR.fl_str_mv Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors
title Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors
spellingShingle Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors
Machado, Lucas de Almeida
HIV-1
Resistência
Inibidores de Integrase
Intasome
Dinâmica molecular
HIV-1
integrase
Intasome
Resistance
Molecular dynamics
Inibidores de Integrase
title_short Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors
title_full Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors
title_fullStr Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors
title_full_unstemmed Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors
title_sort Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors
author Machado, Lucas de Almeida
author_facet Machado, Lucas de Almeida
Guimarães, Ana Carolina Ramos
author_role author
author2 Guimarães, Ana Carolina Ramos
author2_role author
dc.contributor.author.fl_str_mv Machado, Lucas de Almeida
Guimarães, Ana Carolina Ramos
dc.subject.other.pt_BR.fl_str_mv HIV-1
Resistência
Inibidores de Integrase
Intasome
Dinâmica molecular
topic HIV-1
Resistência
Inibidores de Integrase
Intasome
Dinâmica molecular
HIV-1
integrase
Intasome
Resistance
Molecular dynamics
Inibidores de Integrase
dc.subject.en.pt_BR.fl_str_mv HIV-1
integrase
Intasome
Resistance
Molecular dynamics
dc.subject.decs.pt_BR.fl_str_mv Inibidores de Integrase
description Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.
publishDate 2020
dc.date.issued.fl_str_mv 2020
dc.date.accessioned.fl_str_mv 2021-02-01T19:35:46Z
dc.date.available.fl_str_mv 2021-02-01T19:35:46Z
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.citation.fl_str_mv MACHADO, Lucas de Almeida; GUIMARÃES, Ana Carolina. Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors, v. 7, Article 170, 10p, Aug. 2020.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/45910
dc.identifier.issn.pt_BR.fl_str_mv 2296-889X
dc.identifier.doi.none.fl_str_mv 10.3389/fmolb.2020.00170
identifier_str_mv MACHADO, Lucas de Almeida; GUIMARÃES, Ana Carolina. Evidence for Disruption of Mg2C Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors, v. 7, Article 170, 10p, Aug. 2020.
2296-889X
10.3389/fmolb.2020.00170
url https://www.arca.fiocruz.br/handle/icict/45910
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
bitstream.url.fl_str_mv https://www.arca.fiocruz.br/bitstream/icict/45910/1/license.txt
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