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PfMDR1: mechanisms of transport modulation by functional polymorphisms

2011-09Journal article Open access
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dc.contributor.authorFerreira, Pedro
dc.contributor.authorHolmgren, Gabrielle
dc.contributor.authorVeiga, Maria Isabel
dc.contributor.authorUhlen, Per
dc.contributor.authorKaneko, Akira
dc.contributor.authorGil, José Pedro
dc.date.accessioned2018-12-07T14:58:15Z
dc.date.available2018-12-07T14:58:15Z
dc.date.issued2011-09
dc.description.abstractATP-Binding Cassette (ABC) transporters are efflux pumps frequently associated with multidrug resistance in many biological systems, including malaria. Antimalarial drug-resistance involves an ABC transporter, PfMDR1, a homologue of P-glycoprotein in humans. Twenty years of research have shown that several single nucleotide polymorphisms in pfmdr1 modulate in vivo and/or in vitro drug susceptibility. The underlying physiological mechanism of the effect of these mutations remains unclear. Here we develop structural models for PfMDR1 in different predicted conformations, enabling the study of transporter motion. Such analysis of functional polymorphisms allows determination of their potential role in transport and resistance. The bacterial MsbA ABC pump is a PfMDR1 homologue. MsbA crystals in different conformations were used to create PfMDR1 models with Modeller software. Sequences were aligned with ClustalW and analysed by Ali2D revealing a high level of secondary structure conservation. To validate a potential drug binding pocket we performed antimalarial docking simulations. Using aminoquinoline as probe drugs in PfMDR1 mutated parasites we evaluated the physiology underlying the mechanisms of resistance mediated by PfMDR1 polymorphisms. We focused on the analysis of well known functional polymorphisms in PfMDR1 amino acid residues 86, 184, 1034, 1042 and 1246. Our structural analysis suggested the existence of two different biophysical mechanisms of PfMDR1 drug resistance modulation. Polymorphisms in residues 86/184/1246 act by internal allosteric modulation and residues 1034 and 1042 interact directly in a drug pocket. Parasites containing mutated PfMDR1 variants had a significant altered aminoquinoline susceptibility that appears to be dependent on the aminoquinoline lipophobicity characteristics as well as vacuolar efflux by PfCRT. We previously described the in vivo selection of PfMDR1 polymorphisms under antimalarial drug pressure. Now, together with recent PfMDR1 functional reports, we contribute to the understanding of the specific structural role of these polymorphisms in parasite antimalarial drug response.
dc.description.sponsorshipFundacao para a Ciencia e Tecnologia (FCT)/Ministerio da Ciencia e Ensino Superior, Portugal - MCES [SFRH/BD/28368/2006, SFRH/BD/28393/2006]; Swedish Research Council [2005-6682]; Ake Wiberg's Foundation; Fredrik and Ingrid Thuring's Foundation; EDCTP [IP.2007.31060.002]; Styrelsen for Internationellt Utvecklingssamarbete (SIDA) [SWE-2009-165]
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0023875
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/10400.1/11933
dc.language.isoeng
dc.peerreviewedyes
dc.publisherPublic Library of Science
dc.relationCALCIUM OSCILLATIONS IN HUMAN MALARIA PARASITE: IMPLICATIONS FOR THE MECHANISM OF ACTION OF ARTEMISININ AGAINST PLASMODIUM FALCIPARUM
dc.subjectResistant plasmodium-falciparum
dc.subjectIn-vivo selection
dc.subjectP-glycoprotein
dc.subjectArtemether-lumefantrine
dc.subjectChloroquine resistance
dc.subjectMefloquine resistance
dc.subjectSubstrate-specificity
dc.subjectDisrupt Interactions
dc.subjectCombination therapy
dc.subjectQuinine resistance
dc.titlePfMDR1: mechanisms of transport modulation by functional polymorphisms
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCALCIUM OSCILLATIONS IN HUMAN MALARIA PARASITE: IMPLICATIONS FOR THE MECHANISM OF ACTION OF ARTEMISININ AGAINST PLASMODIUM FALCIPARUM
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F28368%2F2006/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F28393%2F2006/PT
oaire.citation.issue9
oaire.citation.startPagee23875
oaire.citation.titlePlos One
oaire.citation.volume6
oaire.fundingStreamSFRH
person.familyNameFerreira
person.familyNameVeiga
person.familyNameGil
person.givenNamePedro
person.givenNameMaria Isabel
person.givenNameJosé Pedro
person.identifier332675
person.identifier.ciencia-id5E15-DD6D-50E6
person.identifier.ciencia-id271C-6028-9C6B
person.identifier.ciencia-idD01A-B30E-BCD5
person.identifier.orcid0000-0002-2682-7722
person.identifier.orcid0000-0002-2205-8102
person.identifier.orcid0000-0002-6107-9379
person.identifier.ridQ-6748-2016
person.identifier.ridH-9922-2018
person.identifier.scopus-author-id55427200100
person.identifier.scopus-author-id12767840900
person.identifier.scopus-author-id7201625436
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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