title: P-glycoprotein models of the apo and ATP-bound states based on homology with Sav1866 and MalK.
abstract: We exploit the biochemical and sequence similarity between Staphylococcus aureus Sav1866 and P-glycoprotein to develop a homology model of P-glycoprotein representing an ATP-bound state, which captures the major features of the low-resolution EM structure and is consistent with cysteine mutagenesis studies. Using insights from the MalK crystal structures and BtuCD simulations, we model two nucleotide-free conformations. Conformational changes are characterized by pincering rigid-body rotations of the nucleotide-binding domains, inducing transmembrane domain reorganizations which correspond to the two lowest frequency normal modes of the protein. These conformations (see supplementary material) may characterize some of the major steps in the nucleotide catalytic cycle.
authors: Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada.
authors: Megan L
authors: ML
authors: O'Mara
authors: D Peter
authors: DP
authors: Tieleman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry*; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D001059:Apoproteins / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry*; D002384:Catalysis; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012997:Solvents; D013211:Staphylococcus aureus / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001059:Apoproteins; D001426:Bacterial Proteins; C068021:MalK protein, Bacteria; D012997:Solvents; D000255:Adenosine Triphosphate