Molecular insight into human P-glycoprotein allosteric transition from outward- to inward-facing state

Abstract

Human P-glycoprotein (P-gp) belongs to ATP-Binding Cassette (ABC) transporter, which can export varieties of anti-cancer drugs out of tumor cells, resulting in multidrug resistance (MDR) of tumor cells. We utilized targeted molecular dynamics simulation to explore the allosteric transition of human P-gp from outward- to inward-facing state. The results show that NBDs experience translational and rotational movement, caused by the successive hydrolysis of ATP molecules. The reorientation of the TMDs begins with the closing of the extracellular gate, followed by the opening of the cytoplasmic gate. The opening delay of the cytoplasmic gate is due to the extensive electrostatic interactions here. The sequence conservation analysis reveals that charged residues in TM3, 4 are highly conserved for achieving the unidirectional transport property. Our results give detailed movement and energy analyses to the reverse allosteric process of human P-gp and are helpful to the understanding of the working mechanism of human P-gp.