Extracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1).

ABSTRACT: Dynamic conformational changes play a major role in the function of proteins, including the ATP-Binding Cassette (ABC) transporters. Multidrug Resistance Protein 1 (MRP1) is an ABC exporter that protects cells from toxic molecules. Overexpression of MRP1 has been shown to confer Multidrug Resistance (MDR), a phenomenon in which cancer cells are capable to defend themselves against a broad variety of drugs. In this study, we used varied computational techniques to explore the unique F583A mutation that is known to essentially lock the transporter in a low-affinity solute binding state. We demonstrate how macro-scale conformational changes affect MRP1's stability and dynamics, and how these changes correspond to micro-scale structural perturbations in helices 10-11 and the nucleotide-binding

SUBMITTER: Bin Kanner Y 

PROVIDER: S-EPMC8187718 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature