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PfMDR1: mechanisms of transport modulation by functional polymorphisms
Pedro Eduardo Ferreira1, Gabrielle Holmgren, Maria Isabel Veiga
1Malaria Research Lab, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. pedro.ferreira@gmail.com
Plos One
|September 14, 2011
Summary
Understanding how mutations in the PfMDR1 transporter affect antimalarial drug resistance is crucial. Structural modeling reveals two distinct mechanisms by which PfMDR1 polymorphisms alter drug susceptibility in malaria parasites.
Area of Science:
- Molecular Biology
- Parasitology
- Structural Biology
Background:
- ATP-Binding Cassette (ABC) transporters, like PfMDR1, are implicated in multidrug resistance in malaria.
- Single nucleotide polymorphisms in pfmdr1 are known to affect antimalarial drug susceptibility, but the mechanisms remain unclear.
Purpose of the Study:
- To develop structural models of PfMDR1 to investigate the functional role of polymorphisms in antimalarial drug resistance.
- To elucidate the biophysical mechanisms underlying PfMDR1-mediated drug resistance.
Main Methods:
- Structural modeling of PfMDR1 using bacterial MsbA ABC pump crystal structures.
- Sequence alignment and secondary structure analysis.
- Antimalarial docking simulations and physiological evaluation of PfMDR1 mutated parasites using aminoquinoline drugs.
Main Results:
- Structural analysis identified two distinct mechanisms of drug resistance modulation by PfMDR1 polymorphisms.
- Polymorphisms at residues 86/184/1246 appear to act via allosteric modulation, while residues 1034/1042 directly interact within a drug-binding pocket.
- Mutated PfMDR1 variants altered aminoquinoline susceptibility, influenced by drug lipophobicity and PfCRT efflux.
Conclusions:
- PfMDR1 polymorphisms contribute to antimalarial drug resistance through distinct structural and biophysical mechanisms.
- This study enhances understanding of the specific structural roles of PfMDR1 polymorphisms in parasite drug response.
- Findings provide insights into the complex interplay of transporters and drug properties in malaria treatment.
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