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.
Highlights
Efflux pumps of the ATP-binding cassette transporters superfamily (ABC transporters) are frequently involved in the multidrug-resistance (MDR) phenomenon in cancer cells
By the superposition of the structural data of the human ABCG2 transporter with our homology model, obtained by duplication of the ABCG5 half transporter (Fig. 2A), all major structural features are found to overlap, with the larger deviations being found at the extracellular coils, the de novo modeled intracellular C2 helices and at the top of the TM5a, before the 5b/5c helical bundle found to be characteristic of the ABCG family
While a slight backbone shift of TM1b and TM3 were observed, an inward-facing cavity was found to be present in our homology model, similar to the one identified in the ABCG2 crystal structure due to the backbone shift of TM helices 2 and 5a, but absent in a previously published homology model[42] obtained from the whole ABCG5/G8 heterodimeric transporter[41]
Summary
Efflux pumps of the ATP-binding cassette transporters superfamily (ABC transporters) are frequently involved in the multidrug-resistance (MDR) phenomenon in cancer cells. ABCG2 in MDR was identified almost simultaneously by several groups in MCF-7/AdrVp cell lines (BCRP or MXR)[5,7] and in placenta (ABCP)[6] In both MCF-7/AdrVp3000 (over-expressing ABCG2) and full length ABCG2 cDNA-transfected MCF-7 breast cancer cells, the over-expression of this transporter conferred resistance to several xenobiotics including mitoxantrone, doxorubicin and daunorubicin, reducing the intracellular accumulation of Rhodamine-123 (R123) by an ATP-dependent mechanism[5,7]. With only a minority dimer population being registered, it was recently determined that tetrameric complexes are the most predominant ones in plasma membranes[17] The possibility that such higher oligomeric forms may serve as a regulator for functional dimeric ABCG2 transporters[13] has become increasingly accepted
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