Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P-glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for its association with MDR due to overexpression in cancer cells. Several P-gp inhibitors or modulators have been investigated in clinical trials in hope of circumventing MDR, with only limited success. Alternative strategies are actively pursued, such as the modification of existing drugs, development of new drugs, or combination of novel drug delivery agents to evade P-gp-dependent efflux. Despite the importance and numerous studies, these efforts have mostly been undertaken without a priori knowledge of how drugs interact with P-gp at the molecular level. This review highlights and discusses progress toward and challenges impeding drug development for inhibiting or evading P-gp in the context of our improved understanding of the structural basis and mechanism of P-gp-mediated MDR.
P-glycoprotein (Pgp) is a highly dynamic ATP-binding cassette transporter that confers cancer multidrug resistance and mediates the bioavailability and pharmacokinetics of many drugs. Structural and biochemical data have provided insights into the binding of diverse compounds, but how they are translocated through the membrane has remained elusive. The biggest hurdle to address this fundamental question has been isolating and characterizing the short-lived transition states during transport. Here, we covalently attached a cyclopeptide substrate to discrete sites of Pgp. Cryo-EM analyses of inward- and outward-facing conformations enabled tracing of the substrate passage and revealed how a cascade of conformational changes in transmembrane helix 1 drives substrate movement across the membrane bilayer upon ATP binding. Observation of a double substrate-bound outward-facing conformation suggests that Pgp can co-transport two compounds simultaneously.One-Sentence SummaryCryo-EM reveals the substrate transport pathway and mechanism of P-glycoprotein from initial binding to release.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.