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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Sauna, Z.E., Kim, IW. & Ambudkar, S.V. Genomics and the mechanism of P-glycoprotein (ABCB1). J Bioenerg Biomembr 39, 481–487 (2007). https://doi.org/10.1007/s10863-007-9115-9
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DOI: https://doi.org/10.1007/s10863-007-9115-9