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Originally published In Press as doi:10.1074/jbc.M100176200 on January 22, 2001

J. Biol. Chem., Vol. 276, Issue 19, 16076-16082, May 11, 2001
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The Structure of the Multidrug Resistance Protein 1 (MRP1/ABCC1)
CRYSTALLIZATION AND SINGLE-PARTICLE ANALYSIS*

Mark F. RosenbergDagger §, Qingcheng Mao, Andreas Holzenburg||, Robert C. FordDagger , Roger G. Deeley, and Susan P. C. Cole

From the Dagger  Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, Manchester M60 1QD, United Kingdom,  Cancer Research Laboratories, Queen's University, Kingston, Ontario K7L 3N6, Canada, and the || Electron Microscopy Center and Department of Biology, Texas A&M University, College Station, Texas 77843-2257

Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-binding cassette (ABC) polytopic membrane transporter of considerable clinical importance that confers multidrug resistance on tumor cells by reducing drug accumulation by active efflux. MRP1 is also an efficient transporter of conjugated organic anions. Like other ABC proteins, including the drug resistance conferring 170-kDa P-glycoprotein (ABCB1), the 190-kDa MRP1 has a core structure consisting of two membrane-spanning domains (MSDs), each followed by a nucleotide binding domain (NBD). However, unlike P-glycoprotein and most other ABC superfamily members, MRP1 contains a third MSD with five predicted transmembrane segments with an extracytosolic NH2 terminus. Moreover, the two nucleotide-binding domains of MRP1 are considerably more divergent than those of P-glycoprotein. In the present study, the first structural details of MRP1 purified from drug-resistant lung cancer cells have been obtained by electron microscopy of negatively stained single particles and two-dimensional crystals formed after reconstitution of purified protein with lipids. The crystals display p2 symmetry with a single dimer of MRP1 in the unit cell. The overall dimensions of the MRP1 monomer are ~80 × 100 Å. The MRP1 monomer shows some pseudo-2-fold symmetry in projection, and in some orientations of the detergent-solubilized particles, displays a stain filled depression (putative pore) appearing toward the center of the molecule, presumably to enable transport of substrates. These data represent the first structural information of this transporter to ~22-Å resolution and provide direct structural evidence for a dimeric association of the transporter in a reconstituted lipid bilayer.

* Supported in part by the Medical Research Council of Canada (Grant MT-10519).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.

§ Recipient of a fellowship from the Royal Society (London, UK). To whom correspondence should be addressed: Tel.: 44-161-200-4186; Fax: 44-161-236-0409; E-mail: mark.rosenberg@umist.ac.uk.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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