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Binding of Steroid Modulators to Recombinant Cytosolic Domain from Mouse P-Glycoprotein in Close Proximity to the ATP Site†

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Laboratoire de Biochimie Structurale et Fonctionnelle, Institut de Biologie et Chimie des Protéines, UPR 412 du Centre National de la Recherche Scientifique, Lyon, France, Institut National de la Santé et de la Recherche Médicale U 33, Le Kremlin-Bicêtre, France, and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada
Cite this: Biochemistry 1997, 36, 49, 15208–15215
Publication Date (Web):December 9, 1997
https://doi.org/10.1021/bi9718696
Copyright © 1997 American Chemical Society
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    Abstract

    We recently found that recombinant NBD1 cytosolic domain corresponding to segment 395−581 of mouse mdr1 P-glycoprotein bound fluorescent 2‘(3‘)-N-methylanthraniloyl-ATP (MANT-ATP) with high affinity [Dayan, G., Baubichon-Cortay, H., Jault, J.-M., Cortay, J.-C., Deléage, G., & Di Pietro, A. (1996) J. Biol. Chem.271, 11652−11658]. The present work shows that a longer 371−705 domain (extended-NBD1), including tryptophan-696 as an intrinsic probe, which bound MANT-ATP with identical affinity, also interacted with steroids known to modulate anticancer drug efflux from P-glycoprotein-positive multidrug-resistant cells. Progesterone, which is not transported, its hydrophobic derivatives medroxyprogesterone acetate and megestrol acetate, and Δ6-progesterone produced nearly a 50% saturating quenching of the domain intrinsic fluorescence, with dissociation constants ranging from 53 to 18 μM. The even more hydrophobic antiprogestin RU 486 produced a complete quenching of tryptophan-696 fluorescence, in contrast to more hydrophilic derivatives of progesterone containing hydroxyl groups at positions 11, 16, 17, and 21 and known to be transported, which produced very little quenching. A similar differential interaction was observed with full-length purified P-glycoprotein. The steroid-binding region within extended-NBD1 appeared distinct from the nucleotide-binding site as the RU 486-induced quenching was neither prevented nor reversed by high ATP concentrations. In contrast, MANT-ATP binding was efficiently prevented or displaced by RU 486, suggesting that the hydrophobic MANT group of the bound nucleotide analogue overlaps, at least partially, the adjacent steroid-binding region revealed by RU 486.

    †

     This work was supported by grants from the CNRS (UPR 412), the Université Claude Bernard de Lyon, and the Fondation de France (Grant 96003891).

    §

     Institut de Biologie et Chimie des Protéines.

    ⊥

     Institut National de la Santé et de la Recherche Médicale U 33.

    ‡

     McGill University.

    *

     Corresponding author address:  Laboratoire de Biochimie Structurale et Fonctionnelle, Institut de Biologie et Chimie des Protéines, UPR 412 du CNRS, Université Claude Bernard-Lyon I, 7 Passage du Vercors, 69367 Lyon Cedex 07, France. Tel:  33-4 72 72 26 29. Fax:  33-4 72 72 26 01. E-mail:  [email protected].

    ✗

     Abstract published in Advance ACS Abstracts, November 15, 1997.

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