Molecular Basis of the Polyspecificity of P-Glycoprotein (ABCB1)

Abstract

ABCB1 (P-glycoprotein/P-gp) is an ATP-binding cassette transporter well known for its association with multidrug resistance in cancer cells. Powered by the hydrolysis of ATP, it effluxes structurally diverse compounds. In this chapter, we discuss current views on the molecular basis of the substrate polyspecificity of P-gp. One of the features that accounts for this property is the structural flexibility observed in P-gp. Several X-ray crystal structures of mouse P-gp have been published recently in the absence of nucleotide, with and without bound inhibitors. All the structures are in an inward-facing conformation exhibiting different degrees of domain separation, thus revealing a highly flexible protein. Biochemical and biophysical studies also demonstrate this flexibility in mouse as well as human P-gp. Site-directed mutagenesis has revealed the existence of multiple transport-active binding sites in P-gp for a single substrate. Thus, drugs can bind at either primary or secondary sites. Biochemical, molecular modeling, and structure-activity relationship studies suggest a large, common drug-binding pocket with overlapping sites for different substrates. We propose that in addition to the structural flexibility, the molecular or chemical flexibility also contributes to the binding of substrates to multiple sites forming the basis of polyspecificity.

Global alteration of the drug-binding pocket of human P-glycoprotein (ABCB1) by substitution of fifteen conserved residues reveals a negative correlation between substrate size and transport efficiency

“…Amino acids in the transmembrane region possibly interacting with substrates were identified based on previously published reports [10, 11, 19–21]. Key amino acids were identified based on their topological location in the homology model of human P-gp generated using the mouse P-gp crystal structure (4Q9H.pdb).…”

“…Mutagenesis and biochemical studies suggest extensive conformational flexibility of P-gp, with two distinct conformations: an inward-facing or open (inverted V shape), and an outward-facing or closed (V shape) conformation (reviewed in [11]). These data also suggest that the transition between these conformations requires ATP hydrolysis [8, 12].…”

Spheres from cervical cancer cells display stemness and cancer drug resistance

“…The mechanisms of drug resistance involve, but are not limited to, the following aspects: The impairment of the DNA repair ability (18), the enrichment of P-glycoprotein (19), the glutathione transferase promotion of the metabolism of anticancer medicine (20) and the existence of CSCs (21). In the present study, the existence of CSCs in drug resistance was preliminarily evaluated.…”

Long Non-Coding RNA MALAT1 Decreases the Sensitivity of Resistant Glioblastoma Cell Lines to Temozolomide

“…Multiple multidrug resistance-associated proteins that mediate MDR through different mechanisms have been previously identified. MDR1 is a typical ATP-binding cassette (ABC)-transporter that pumps foreign substances out of cells; it is responsible for the reduced drug accumulation in cancer cells and for mediating the development of MDR [21]. MRP5, a transporter for cyclic nucleotides, belongs to the subfamily of MRP and functions in the cellular export of its substrate.…”