P-glycoprotein must open further to bind large substrates

Surface rendering of the crystal structure of P-glycoprotein in the absence of drugs (tan colored). Various drug molecules are placed around the protein (brown) in the approximate location of the inner leaflet of the bilayer. The structure reveals that, although two narrow doors (on each side of the protein) open to the inner leaflet for entry of very small compounds, the doors must open even wider for the larger substrates to enter the internal poly-specific drug-binding cavity.

from largest to smallest:

Cyclosporin A (cyan)

Vinblastine (orange)

Verapamil (green)

"QZ59-RRR" cyclic peptide (magenta)

Phosphatidyl choline (grey)

Hoechst (yellow)

tetra-phenyl-phosphate (blue)

tetramethyl lead (chocolate)

CMNP (red)

ethyl mercuric chloride (olive)

methyl mercuric chloride (purple)