Mutational analysis of polar amino acid residues within predicted transmembrane helices of Multidrug Resistance Protein 1 (ABCC1): Effect on substrate specificity

TL;DRAbstract

Human Multidrug Resistance Protein1 (MRP1) is an ATP Binding Cassette (ABC) transporter that confers resistance to many natural product chemotherapeutic agents and can transport structurally diverse conjugated organic anions. In addition to two cytoplasmic nucleotide binding domains (NBDs), MRP1 has three polytopic membrane‐spanning domains (MSDs) with a total of 17 transmembrane (TM) helices. Using site‐directed mutagenesis, we demonstrated that certain polar residues within a number of TM helices are determinants of MRP1 substrate specificity or overall activity. For example, mutations T550A and T556A in TM10, N597A and S605A in TM11, E1089Q and K1092 in TM14, as well as Y1236F and T1241A in TM17 only modulated the drug resistance profile of MRP1. In contrast, Y568A in TM10, S1097A and N1100A in TM14, as well as T1242A in TM17 only altered the ability of MRP1 to transport the conjugated organic anion, 17β‐estradiol 17‐(β‐D‐glucuronide) (E 2 17βG). On the other hand, some mutations, s

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