Molecular model of the outward facing state of the human P-glycoprotein (ABCB1), and comparison to a model of the human MRP5 (ABCC5) - PubMed (original) (raw)
Molecular model of the outward facing state of the human P-glycoprotein (ABCB1), and comparison to a model of the human MRP5 (ABCC5)
Aina W Ravna et al. Theor Biol Med Model. 2007.
Abstract
Background: Multidrug resistance is a particular limitation to cancer chemotherapy, antibiotic treatment and HIV medication. The ABC (ATP binding cassette) transporters human P-glycoprotein (ABCB1) and the human MRP5 (ABCC5) are involved in multidrug resistance.
Results: In order to elucidate structural and molecular concepts of multidrug resistance, we have constructed a molecular model of the ATP-bound outward facing conformation of the human multidrug resistance protein ABCB1 using the Sav1866 crystal structure as a template, and compared the ABCB1 model with a previous ABCC5 model. The electrostatic potential surface (EPS) of the ABCB1 substrate translocation chamber, which transports cationic amphiphilic and lipophilic substrates, was neutral with negative and weakly positive areas. In contrast, EPS of the ABCC5 substrate translocation chamber, which transports organic anions, was generally positive. Positive-negative ratios of amino acids in the TMDs of ABCB1 and ABCC5 were also analyzed, and the positive-negative ratio of charged amino acids was higher in the ABCC5 TMDs than in the ABCB1 TMDs. In the ABCB1 model residues Leu65 (transmembrane helix 1 (TMH1)), Ile306 (TMH5), Ile340 (TMH6) and Phe343 (TMH6) may form a binding site, and this is in accordance with previous site directed mutagenesis studies.
Conclusion: The Sav1866 X-ray structure may serve as a suitable template for the ABCB1 model, as it did with ABCC5. The EPS in the substrate translocation chambers and the positive-negative ratio of charged amino acids were in accordance with the transport of cationic amphiphilic and lipophilic substrates by ABCB1, and the transport of organic anions by ABCC5.
Figures
Figure 1
Evolutionary tree. Evolutionary tree of the human ABC efflux permeases, together with Sav1866. The topmost branch (the "ABCB-branch") includes ABCB1 and Sav1866, while the next branch (the "ABCC-branch") includes ABCC5.
Figure 2
ABCB1 and ABCC5 models. Cα traces of the ABCB1 (Panel A) and ABCC5 (Panel B) models viewed in the membrane plane, with the extracellular side facing upwards. Color code of the models is blue via white to red from N-terminal to C-terminal.
Figure 3
Electrostatic potentials surface (EPS). The electrostatic potentials surface (EPS) of the substrate translocation chambers of ABCB1 (Panel A) and ABCC5 (Panel B) viewed from the intracellular side with blue areas indicating positive areas and red areas indicating negative areas. TMHs are displayed as green ribbons. TMH numbering is indicated in white boxes.
Figure 4
Ligand interaction areas. Close-up of putative ligand interaction areas of ABCB1 (Panel A) and ABCC5 (Panel B). The view is a cross-section of the transporters perpendicular to the membrane. The oval shaped object with the text "Verapamil" (Panel A) indicates where Verapamil binding may take place. TMHs are shown as blue Cα traces. Color coding of displayed residues: Carbon: White; Hydrogen: Grey; Oxygen: Red; Nitrogen: Blue. Panel A: Residues Leu65 (TMH1) [30], Ile306 (TMH5) [30], Ile340 (TMH6) [25, 30] and Phe343 (TMH6) [26] have been shown to interact with ligands in site directed mutagenesis studies. Panel B: Corresponding residues in ABCC5 are Gln190 (TMH1), Val410 (TMH5), Asn441 (TMH6) and Thr444 (TMH6) respectively.
Figure 5
Alignment. Alignment of VC-Sav1866, ABCB1 and ABCC5 used as input alignment for the ICM homology modeling module. TMHs are indicated in red boxes, Walker A motifs are indicated in yellow boxes, and Walker B motifs are indicated in green boxes.
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References
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