Structure of ABCB1/P-Glycoprotein in the Presence of the CFTR Potentiator Ivacaftor

Alessandro Barbieri, Nopnithi Thonghin, Talha Shafi, Stephen M. Prince, Richard Collins, Robert Ford

Research output: Contribution to journalArticlepeer-review


ABCB1/P-glycoprotein is an ATP binding cassette transporter that is involved in the clearance of xenobiotics, and it affects the disposition of many drugs in the body. Conformational flexibility of the protein within the membrane is an intrinsic part of its mechanism of action, but this has made structural studies challenging. Here, we have studied different conformations of P-glycoprotein simultaneously in the presence of ivacaftor, a known competitive inhibitor. In order to conduct this, we used high contrast cryo-electron microscopy imaging with a Volta phase plate. We associate the presence of ivacaftor with the appearance of an additional density in one of the conformational states detected. The additional density is in the central aqueous cavity and is associated with a wider separation of the two halves of the transporter in the inward-facing state. Conformational changes to the nucleotide-binding domains are also observed and may help to explain the stimulation of ATPase activity that occurs when transported substrate is bound in many ATP binding cassette transporters.

Original languageEnglish
Article number923
Issue number12
Publication statusPublished - 25 Nov 2021


  • ABC transporter
  • ABCB1
  • ABCC7
  • Drug binding
  • Ivacaftor
  • P-glycoprotein
  • Volta phase plate

Research Beacons, Institutes and Platforms

  • Manchester Institute of Biotechnology


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