Genomics and the mechanism of P-glycoprotein (ABCB1) |
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Authors: | Zuben E Sauna In-Wha Kim Suresh V Ambudkar |
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Institution: | (1) Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Building 37, Room 2120, 37 Convent Drive, Bethesda, MD 20892-4256, USA |
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Abstract: | The development of effective clinical interventions against multidrug resistance (MDR) in cancer remains a significant challenge.
Single nucleotide polymorphisms (SNPs) contribute to wide variations in how individuals respond to medications and there are
several SNPs in human P-glycoprotein (P-gp) that may influence the interactions of drug-substrates with the transporter. Interestingly,
even some of the synonymous SNPs have functional consequences for P-gp. It is also becoming increasingly evident that an understanding
of the transport pathway of P-gp may be necessary to design effective modulators. In this review we discuss: (1) The potential
importance of SNPs (both synonymous and non-synonymous) in MDR and (2) How new concepts that have emerged from structural
studies with isolated nucleotide binding domains of bacterial ABC transporters have prompted biochemical studies on P-gp,
leading to a better understanding of the mechanism of P-gp mediated transport. Our results suggest that the power-stroke is
provided only after formation of the pre-hydrolysis transition-like (E·S) state during ATP hydrolysis. |
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Keywords: | ATP-binding cassette P-glycoprotein Multidrug resistance ATP hydrolysis Catalytic/transport pathway Single nucleotide polymorphism |
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