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Originally published In Press as doi:10.1074/jbc.M206058200 on July 22, 2002

J. Biol. Chem., Vol. 277, Issue 38, 35225-35231, September 20, 2002
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Photolabeling of Human and Murine Multidrug Resistance Protein 1 with the High Affinity Inhibitor [125I]LY475776 and Azidophenacyl-[35S]Glutathione*

Yue-Ming QianDagger , Caroline E. GrantDagger , Christopher J. Westlake§Dagger , Da-Wei ZhangDagger , Peter A. Lander||, Robert L. Shepard||, Anne H. Dantzig||, Susan P. C. ColeDagger **, and Roger G. DeeleyDagger Dagger Dagger

From the Dagger  Cancer Research Laboratories and Departments of  Pathology and § Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6 and || Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0424

Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-dependent transporter of structurally diverse organic anion conjugates. The protein also actively transports a number of non-conjugated chemotherapeutic drugs and certain anionic conjugates by a presently poorly understood GSH-dependent mechanism. LY475776is a newly developed 125I-labeled azido tricyclic isoxazole that binds toMRP1 with high affinity and specificity in a GSH-dependent manner. The compound has also been shown to photolabel a site in the COOH-proximal region of MRP1's third membrane spanning domain (MSD). It is presently not known where GSH interacts with the protein. Here, we demonstrate that the photactivateable GSH derivative azidophenacyl-GSH can substitute functionally for GSH in supporting the photolabeling of MRP1 by LY475776 and the transport of another GSH-dependent substrate, estrone 3-sulfate. In contrast to LY475776, azidophenacyl-[35S] photolabels both halves of the protein. Photolabeling of the COOH-proximal site can be markedly stimulated by low concentrations of estrone 3-sulfate, suggestive of cooperativity between the binding of these two compounds. We show that photolabeling of the COOH-proximal site by LY475776 and the labeling of both NH2- and COOH- proximal sites by azidophenacyl-GSH requires the cytoplasmic linker (CL3) region connecting the first and second MSDs of the protein, but not the first MSD itself. Although required for binding, CL3 is not photolabeled by azidophenacyl-GSH. Finally, we identify non-conserved amino acids in the third MSD that contribute to the high affinity with which LY475776 binds to MRP1.

* This work was supported by a grant from the National Cancer institute of Canada with funds from the Terry Fox Foundation and a grant from Eli Lilly Inc.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** Canada Research Chair in Cancer Biology and Senior Scientist of Cancer Care Ontario.

Dagger Dagger Stauffer Research Professor of Queen's University. To whom correspondence should be addressed: Cancer Research Labs, Queens University, Rm. A315 Botterell Hall, Stuart and George Streets, ON, Canada K7L 3N6. Tel.: 613-533-2979; Fax: 613-533-6830; E-mail: deeleyr@post.queensu.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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