Structure of a human multidrug transporter in an inward-facing conformation

Faculty of Life Sciences, Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
Journal of Structural Biology (Impact Factor: 3.23). 06/2010; 170(3):540-7. DOI: 10.1016/j.jsb.2010.01.011
Source: PubMed


Multidrug resistance protein 1 (ABCC1) is a member of the 'C' class of ATP-binding cassette transporters, which can give rise to resistance to chemotherapy via drug export from cells. It also acts as a leukotriene C4 transporter, and hence has a role in adaptive immune response. Most C-class members have an additional NH(2)-terminal transmembrane domain versus other ATP-binding cassette transporters, but little is known about the structure and role of this domain. Using electron cryomicroscopy of 2D crystals, data at 1/6per A(-1) resolution was generated for the full-length ABCC1 protein in the absence of ATP. Analysis using homologous structures from bacteria and mammals allowed the core transmembrane domains to be localised in the map. These display an inward-facing conformation and there is a noteworthy separation of the cytoplasmic nucleotide-binding domains. Examination of non-core features in the map suggests that the additional NH(2)-terminal domain has extensive contacts on one side of both core domains, and mirrors their inward-facing configuration in the absence of nucleotide.

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    • "It plays, however , an important role in processing and trafficking of the transporter. The most recent structure of MRP1 obtained by cryoelectron microscopy of 2D crystals (Rosenberg et al., 2010) has revealed an inward-facing structure with separated NBD domains similar to the structure obtained previously for P-gp (Aller et al., 2009). Unfortunately, the resolution of the MRP1 structure (1/6 per Å –1 ) was too low to allow for identification of protein fragments engaged in the formation of the drug binding pocket. "
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    • "However, it is possible that regulatory domains of ABC proteins may act in a similar fashion, by influencing the dimerisation of the NBDs [7] [10] [11]. Medium resolution data from 2D crystals of another member of the 'C' subclass of ABC proteins have also been recently published [12]. Low-resolution structural data from 2D crystals and single-particle analysis of the whole CFTR protein have been reported. "
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