PfMDR1: mechanisms of transport modulation by functional polymorphisms.

ATP-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...

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Autores principales:	Pedro Eduardo Ferreira, Gabrielle Holmgren, Maria Isabel Veiga, Per Uhlén, Akira Kaneko, José Pedro Gil
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cd80b8e866e44f16966a73e87bac27d6
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spelling	oai:doaj.org-article:cd80b8e866e44f16966a73e87bac27d62021-11-18T06:46:48ZPfMDR1: mechanisms of transport modulation by functional polymorphisms.1932-620310.1371/journal.pone.0023875https://doaj.org/article/cd80b8e866e44f16966a73e87bac27d62011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21912647/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203ATP-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.Pedro Eduardo FerreiraGabrielle HolmgrenMaria Isabel VeigaPer UhlénAkira KanekoJosé Pedro GilPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e23875 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pedro Eduardo Ferreira Gabrielle Holmgren Maria Isabel Veiga Per Uhlén Akira Kaneko José Pedro Gil PfMDR1: mechanisms of transport modulation by functional polymorphisms.
description	ATP-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.
format	article
author	Pedro Eduardo Ferreira Gabrielle Holmgren Maria Isabel Veiga Per Uhlén Akira Kaneko José Pedro Gil
author_facet	Pedro Eduardo Ferreira Gabrielle Holmgren Maria Isabel Veiga Per Uhlén Akira Kaneko José Pedro Gil
author_sort	Pedro Eduardo Ferreira
title	PfMDR1: mechanisms of transport modulation by functional polymorphisms.
title_short	PfMDR1: mechanisms of transport modulation by functional polymorphisms.
title_full	PfMDR1: mechanisms of transport modulation by functional polymorphisms.
title_fullStr	PfMDR1: mechanisms of transport modulation by functional polymorphisms.
title_full_unstemmed	PfMDR1: mechanisms of transport modulation by functional polymorphisms.
title_sort	pfmdr1: mechanisms of transport modulation by functional polymorphisms.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/cd80b8e866e44f16966a73e87bac27d6
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PfMDR1: mechanisms of transport modulation by functional polymorphisms.

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