Structure and function of the human breast cancer resistance protein (BCRP/ABCG2)

Abstract

The human breast cancer resistance protein (BCRP/ABCG2) is the second member of the G subfamily of the large ATP-binding cassette (ABC) transporter superfamily. BCRP was initially discovered in multidrug resistant breast cancer cell lines where it confers resistance to chemotherapeutic agents such as mitoxantrone, topotecan and methotrexate by extruding these compounds out of the cell. BCRP is capable of transporting non-chemotherapy drugs and xenobiotiocs as well, including nitrofurantoin, prazosin, glyburide, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. BCRP is frequently detected at high levels in stem cells, likely providing xenobiotic protection. BCRP is also highly expressed in normal human tissues including the small intestine, liver, brain endothelium, and placenta. Therefore, BCRP has been increasingly recognized for its important role in the absorption, elimination, and tissue distribution of drugs and xenobiotics. At present, little is known about the transport mechanism of BCRP, particularly how it recognizes and transports a large number of structurally and chemically unrelated drugs and xenobiotics. Here, we review current knowledge of structure and function of this medically important ABC efflux drug transporter.

Fig. 1

Chemical structures of representative BCRP substrates.

Fig. 2

Chemical structures of representative BCRP inhibitors.

Fig. 3

Schematic illustration of the membrane topology of BCRP. The boundary of transmembrane α-helices is approximate and based on the experimentally determined membrane topology of BCRP. The ATP site (the Walker A and Walker B motifs), and the C signature motif are indicated. Lys substitution of Gln¹⁴¹ (Q141K), a natural variant with decreased protein expression, causes changes in the pharmacokinetics of BCRP substrate drugs in vivo. Arg⁴⁸² is critical for substrate specificity and transport activity of BCRP. Asn⁵⁹⁶ is the N-linked glycosylation site. Cys⁶⁰³ is possibly involved in dimerization/oligomerization of BCRP through intermolecular disulfide bonds.

Fig. 4

Schematic representation of the homology models of BCRP. A, the substrate-unbound nucleotide-free inward-facing open apo conformation based on the MsbA structure (PDB code 3B5W); B, the substrate-bound nucleotide-free inward-facing closed apo conformation based on the mouse P-gp structure (PDB code 3G60). The approximate locations of several amino acid residues in the MSD (Ser⁴⁴¹, Glu⁴⁴⁶, His⁴⁵⁷, Phe⁴⁸⁹, and Arg⁴⁸²) or the NBD (Lys⁸⁶ and Glu²¹¹) that could be important for substrate specificity and/or overall transport activity are indicated; C, the nucleotide-bound outward-facing conformation based on the Sav1866 structure (PDB code 2HYD). Two monomers in the BCRP dimer are shown in different colors.