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Molecular model of the outward facing state of the human P-glycoprotein (ABCB1), and comparison to a model of the human MRP5 (ABCC5).

Ravna AW, Sylte I, Sager G - Theor Biol Med Model (2007)

Bottom Line: 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 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway. Aina.W.Ravna@fagmed.uit.no

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.

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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.
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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.

Mentions: The evolutionary tree of the human ABC transporters, together with Sav1866, is shown in Figure 1. ABCB1 and Sav1866 are localized on the same branch of the evolutionary tree (the "ABCB-branch"), while ABCC5 is localized on a different branch (the "ABCC-branch").


Molecular model of the outward facing state of the human P-glycoprotein (ABCB1), and comparison to a model of the human MRP5 (ABCC5).

Ravna AW, Sylte I, Sager G - Theor Biol Med Model (2007)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2211457&req=5

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.
Mentions: The evolutionary tree of the human ABC transporters, together with Sav1866, is shown in Figure 1. ABCB1 and Sav1866 are localized on the same branch of the evolutionary tree (the "ABCB-branch"), while ABCC5 is localized on a different branch (the "ABCC-branch").

Bottom Line: 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 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway. Aina.W.Ravna@fagmed.uit.no

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.

Show MeSH