Tracing the substrate translocation mechanism in P-glycoprotein (Updated October 31, 2023).

This article discusses the substrate translocation mechanism in P-glycoprotein (Pgp), an ATP-dependent organic anion transporter that plays a significant role in cancer multidrug resistance and drug bioavailability. The researchers used cryoEM and molecular dynamics simulations to study the structure and conformational changes of Pgp during substrate transport. They found that a specific transmembrane helix, TM1, is crucial for regulating substrate transport, and identified a novel mechanism where the substrate can exit Pgp without requiring a wide-open outward-facing conformation. This research provides valuable insights for future drug discovery studies targeting Pgp. Please note that this article is a preprint and has not undergone peer review. [Extracted from the article]