PfMDR1 Mechanisms of Transport Modulation by Functional Polymorphisms 英文参考文献.docVIP

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PfMDR1 Mechanisms of Transport Modulation by Functional Polymorphisms 英文参考文献.doc

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PfMDR1 Mechanisms of Transport Modulation by Functional Polymorphisms 英文参考文献

PfMDR1:MechanismsofTransportModulationby FunctionalPolymorphisms PedroEduardoFerreira1,2,4*,GabrielleHolmgren1,MariaIsabelVeiga1,4,PerUhle′n3,AkiraKaneko2,Jose′ PedroGil4,5,6 1MalariaResearchLab,DepartmentofMedicine,KarolinskaInstitutet,Stockholm,Sweden, 2InstituteforMicrobiology,TumourandCellBiology,KarolinskaInstitutet, Stockholm,Sweden,3DepartmentofMedicalBiochemistryandBiophysics,KarolinskaInstitutet,Stockholm,Sweden,4DrugResistanceandPharmacogeneticsGroup, Institute of Biotechnology and Bioengineering, Centre of Molecular and Structural Biomedicine, University of Algarve, Faro, Portugal, 5Unit of Pharmacogenetics, DepartmentofPhysiologyandPharmacology,KarolinskaInstitutet,Stockholm,Sweden,6DepartmentofBiologicalSciences,TheHarpurCollegeofArtsandSciences, BinghamtonUniversity,Binghamton,NewYork,UnitedStatesofAmerica Abstract ATP-Binding Cassette (ABC) transporters are efflux pumps frequently associated with multidrug resistance in many biologicalsystems,includingmalaria.Antimalarialdrug-resistanceinvolvesanABCtransporter,PfMDR1,ahomologueofP- 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 mutationsremainsunclear.HerewedevelopstructuralmodelsforPfMDR1indifferentpredictedconformations,enabling thestudyoftransportermotion.Suchanalysisoffunctionalpolymorphismsallowsdeterminationoftheirpotentialrolein transportandresistance.ThebacterialMsbAABCpumpisaPfMDR1homologue.MsbAcrystalsindifferentconformations wereusedtocreatePfMDR1modelswithModellersoftware.SequenceswerealignedwithClustalWandanalysedbyAli2D 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 physiologyunderlyingthemechanismsofresistancemediate