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Conformational dynamics of P-glycoprotein in lipid nanodiscs and detergent micelles reveal complex motions on a wide time scale. | LitMetric

AI Article Synopsis

  • * In this study, researchers examined the local movements of P-gp's inward-facing state using a technique called hydrogen-deuterium (H/D) exchange mass spectrometry, finding complex dynamics suggesting multiple conformational states.
  • * The experiments showed that adding ATP altered P-gp's dynamics, potentially affecting how it interacts with various substrates, indicating that its ability to bind many different drugs could be due to its dynamic conformations.

Article Abstract

P-glycoprotein (P-gp) is a highly substrate-promiscuous efflux transporter that plays a critical role in drug disposition. P-gp utilizes ATP hydrolysis by nucleotide-binding domains (NBDs) to drive transitions between inward-facing (IF) conformations that bind drugs and outward-facing (OF) conformations that release them to the extracellular solution. However, the details of the protein dynamics within either macroscopic IF or OF conformation remain uncharacterized, and the functional role of local dynamics has not been determined. In this work we measured the local dynamics of the IF state of P-gp in lipid nanodiscs and in detergent solution by hydrogen-deuterium (H/D) exchange MS. We observed "EX1 exchange kinetics," or bimodal kinetics, for several peptides distributed in both NBDs, particularly for P-gp in the lipid nanodiscs. Remarkably, the EX1 kinetics occurred on several time scales, ranging from seconds to hours, suggesting highly complex, and correlated, motions. The results indicate at least three distinct conformational states in the ligand-free P-gp and suggest a rough conformational landscape. Addition of excess ATP and vanadate, to favor the OF conformations, caused a generalized, but modest, decrease in H/D exchange throughout the NBDs and slowed the EX1 kinetic transitions of several peptides. The functional implications of the results are consistent with the possibility that conformational selection provides a source of substrate promiscuity.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925813PMC
http://dx.doi.org/10.1074/jbc.RA118.002190DOI Listing

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