Genomics and the mechanism of P-glycoprotein (ABCB1).
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.
Sauna
Zuben E
ZE
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Building 37, 37 Convent Drive, Bethesda, MD 20892-4256, USA.
Kim
In-Wha
IW
Ambudkar
Suresh V
SV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D001692:Biological Transport; D018432:Drug Resistance, Multiple / Q000235:genetics; D019450:Genes, MDR; D015894:Genome, Human; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001426:Bacterial Proteins