Molecular modeling of the human multidrug resistance protein 1 (MRP1/ABCC1).
Multidrug resistance protein 1 (MRP1/ABCC1) is a 190kDa member of the ATP-binding cassette (ABC) superfamily of transmembrane transporters that is clinically relevant for its ability to confer multidrug resistance by actively effluxing anticancer drugs. Knowledge of the atomic structure of MRP1 is needed to elucidate its transport mechanism, but only low resolution structural data are currently available. Consequently, comparative modeling has been used to generate models of human MRP1 based on the crystal structure of the ABC transporter Sav1866 from Staphylococcus aureus. In these Sav1866-based models, the arrangement of transmembrane helices differs strikingly from earlier models of MRP1 based on the structure of the bacterial lipid transporter MsbA, both with respect to packing of the twelve helices and their interactions with the nucleotide binding domains. The functional importance of Tyr324 in transmembrane helix 6 predicted to project into the substrate translocation pathway was investigated.
DeGorter
Marianne K
MK
Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Ont, Canada K7L 3N6.
Conseil
Gwenaëlle
G
Deeley
Roger G
RG
Campbell
Robert L
RL
Cole
Susan P C
SP
D001426:Bacterial Proteins / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry*; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000737:chemistry; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014443:Tyrosine; C421109:multidrug resistance-associated protein 1