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Sci Rep. 2017 Nov 14;7(1):15534. doi: 10.1038/s41598-017-15452-z.

Structure-function relationships in ABCG2: insights from molecular dynamics simulations and molecular docking studies.

Author information

1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
2
LAQV@REQUIMTE, Department of Chemistry & Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal.
3
LAQV@REQUIMTE, Department of Chemistry & Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal. ncordeir@fc.up.pt.
4
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal. ddsantos@fc.up.pt.
5
LAQV@REQUIMTE, Department of Chemistry & Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal. ddsantos@fc.up.pt.

Abstract

Efflux pumps of the ATP-binding cassette transporters superfamily (ABC transporters) are frequently involved in the multidrug-resistance (MDR) phenomenon in cancer cells. Herein, we describe a new atomistic model for the MDR-related ABCG2 efflux pump, also named breast cancer resistance protein (BCRP), based on the recently published crystallographic structure of the ABCG5/G8 heterodimer sterol transporter, a member of the ABCG family involved in cholesterol homeostasis. By means of molecular dynamics simulations and molecular docking, a far-reaching characterization of the ABCG2 homodimer was obtained. The role of important residues and motifs in the structural stability of the transporter was comprehensively studied and was found to be in good agreement with the available experimental data published in literature. Moreover, structural motifs potentially involved in signal transmission were identified, along with two symmetrical drug-binding sites that are herein described for the first time, in a rational attempt to better understand how drug binding and recognition occurs in ABCG2 homodimeric transporters.

PMID:
29138424
PMCID:
PMC5686161
DOI:
10.1038/s41598-017-15452-z
[Indexed for MEDLINE]
Free PMC Article

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