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Volume 272, Number 33, Issue of August 15, 1997 pp. 20913-20919
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Localization of the Iodomycin Binding Site in Hamster P-glycoprotein

(Received for publication, April 17, 1997, and in revised form, May 30, 1997)

Annette Demmer , Hubert Thole ^¶ , Peter Kubesch , Tanja Brandt , Manfred Raida , Rainer Fislage and Burkhard Tümmler

From the  Klinische Forschergruppe, Zentrum Biochemie and Zentrum Kinderheilkunde, OE 4350, Medizinische Hochschule Hannover, D-30623 Hannover, ^¶ Max-Planck-Institut für experimentelle Endokrinologie, D-30625 Hannover and  Niedersächsisches Institut für Peptidforschung, D-30625 Hannover, Germany

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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