Publication: Structure of abcb1/p-glycoprotein in the presence of the cftr potentiator ivacaftor
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Issued Date
2021
Resource Type
Language
eng
File Type
application/pdf
ISSN
20770375
Other identifier(s)
2-s2.0-85120695193
Rights Holder(s)
Scopus
Bibliographic Citation
Membranes. Vol 11, No.12 (2021)
Suggested Citation
Barbieri A., Thonghin N., Shafi T., Prince S.M., Collins R.F., Ford R.C. Structure of abcb1/p-glycoprotein in the presence of the cftr potentiator ivacaftor. Membranes. Vol 11, No.12 (2021). doi:10.3390/membranes11120923 Retrieved from: https://hdl.handle.net/20.500.14740/6085
Abstract
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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.