Structure of a human multidrug transporter in an inward-facing conformation.
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.
Rosenberg
Mark F
MF
Faculty of Life Sciences, Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
Oleschuk
Curtis J
CJ
Wu
Peng
P
Mao
Qingcheng
Q
Deeley
Roger G
RG
Cole
Susan P C
SP
Ford
Robert C
RC
D000255:Adenosine Triphosphate / Q000378:metabolism; D001483:Base Sequence; D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D021621:Imaging, Three-Dimensional; D066298:In Vitro Techniques; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure*; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D040681:Structural Homology, Protein
D000255:Adenosine Triphosphate; D017931:DNA Primers; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011994:Recombinant Proteins; C421109:multidrug resistance-associated protein 1