Structural Characterization of the Drug Translocation Path of MRP1/ABCC1. Issue 8 (12th May 2014)

• Record Type: Journal Article
• Authors: Amram, Shay; Ganoth, Assaf; Tichon, Or; Peer, Dan; Nachliel, Esther; Gutman, Menachem; Tsfadia, Yossi
• Is Part Of: Israel journal of chemistry. Volume 54:Issue 8/9(2014)
• Page Start: 1382
• Page End: 1393
• Publication Date: 2014-05-12
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1002/ijch.201300132
• Languages: English
• ISSNs: 0021-2148

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>The rapid clearance of drugs from human cells is carried out by MRP1 and other proteins of the ABC transporter superfamily. Selective mutations carried out by DeGorter indicated that replacement of Y324 by phenylalanine (but not by tryptophan or alanine) enhances the capacity of the protein to extrude various drugs. In this study we investigate the effect of mutation on the structure of the isolated transmembrane domain of MRP1 through molecular dynamics simulations of the protein embedded in a POPC membrane. The simulations reveal a persistent tendency of the translocation path to experience a partial constriction, losing ∼50 % of the water inside the conducting path. While the Wt, Y324W and Y324A transporters all experienced the same constriction, the Y324F transporter, the one having a higher clearance rate than the Wt, retains a fully open configuration. The structure of the Y324F mutant reveals an alternate set of stabilizing interactions that force a kink in transmembrane helix 6, which keeps the protein in a fully open outward‐facing configuration thus providing a molecular‐level account for the higher activity of the mutant. The ability of the simulations to corroborate the experimental observations implies that the homology model of MRP1 is a proper representation of the internal interactions between the residues in the protein, and can be used as a reliable model for studying the human multidrug resistance function of the MRP1 protein.</p> </abstract>