Abstract
The structure of P-glycoprotein (Pgp) from mouse has been studied by electron microscopy and image analysis. Two-dimensional crystals of Pgp in a lipid bilayer were generated by reconstituting pure, detergent-solubilized protein containing a C-terminal six-histidine tag using the lipid monolayer technique. The crystals belong to plane group P1 with a = b = 104 +/- 2 A and gamma = 90 +/- 4 degrees. The projection structure of Pgp calculated at a resolution of 22 A shows two closely interacting protein domains that can be interpreted as the N- and C-terminal halves of the protein. The projection structure of Pgp is consistent with the recently published x-ray structure of MsbA, a lipid A flippase from Escherichia coli with high sequence homology to Pgp but only when the two MsbA subunits are rotated to bring their nucleotide binding domains together.
Highlights
The structure of P-glycoprotein (Pgp) from mouse has been studied by electron microscopy and image analysis
ATP binding cassette (ABC) transporters typically consist of four domains, two nucleotide binding domains (NBDs) located in the cytoplasm and two transmembrane domains (TMDs) responsible for binding and transport of transport substrates and/or drugs
The N- and C-terminal halves of Pgp show strong sequence homology to each other and in bacterial ABC transporters, the functional domains are often composed of pairs of identical separate polypeptides
Summary
The structure of P-glycoprotein (Pgp) from mouse has been studied by electron microscopy and image analysis. The x-ray model of MsbA shows that its TMDs contain six bilayer-spanning ␣-helices, and this membrane topology is predicted for Pgp. The arrangement of the functional domains is quite different in the 3.2-Å resolution model of BtuCD that shows the two nucleotide binding subunits (BtuD) in close contact with each other, giving the protein a much more compact appearance.
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