Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein

Acta Crystallogr D Biol Crystallogr. 2015 Mar;71(Pt 3):732-41. doi: 10.1107/S1399004715000978. Epub 2015 Feb 26.


P-glycoprotein (P-gp) is a transporter of great clinical and pharmacological significance. Several structural studies of P-gp and its homologs have provided insights into its transport cycle, but questions remain regarding how P-gp recognizes diverse substrates and how substrate binding is coupled to ATP hydrolysis. Here, four new P-gp co-crystal structures with a series of rationally designed ligands are presented. It is observed that the binding of certain ligands, including an ATP-hydrolysis stimulator, produces a large conformational change in the fourth transmembrane helix, which is positioned to potentially transmit a signal to the nucleotide-binding domains. A new ligand-binding site on the surface of P-gp facing the inner leaflet of the membrane is also described, providing vital insights regarding the entry mechanism of hydrophobic drugs and lipids into P-gp. These results represent significant advances in the understanding of how P-gp and related transporters bind and export a plethora of metabolites, antibiotics and clinically approved and pipeline drugs.

Keywords: P-glycoprotein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / chemistry
  • Adenosine Triphosphate / chemistry*
  • Crystallography, X-Ray
  • Humans
  • Protein Structure, Secondary
  • Protein Structure, Tertiary


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Adenosine Triphosphate