P-glycoprotein, the overexpression of which is a major cause for the failure of cancer chemotherapy in man, recognizes and transports a broad range of structurally unrelated amphiphilic compounds. This study reports on the localization of the binding site of P-glycoprotein for iodomycin, the Bolton-Hunter derivative of the anthracycline daunomycin. Plasma membrane vesicles isolated from multidrug-resistant Chinese hamster ovary B30 cells were photolabeled with [125I]iodomycin. After chemical cleavage behind the tryptophan residues, 125I-labeled peptides were separated by electrophoresis and high performance liquid chromatography. Edman sequencing revealed that [125I]iodomycin had been predominantly incorporated into the fragment 230-312 of isoform I of hamster P-glycoprotein. According to models based on hydropathy plots, the amino acid sequence 230-312 forms the distal part of transmembrane segment 4, the second cytoplasmic loop, and the proximal part of transmembrane segment 5 in the N-terminal half of P-glycoprotein. The binding site for iodomycin is recognized with high affinity by vinblastine and cyclosporin A.
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