Cholesterol Asymmetrically Modulates the Conformational Ensemble of the Nucleotide-Binding Domains of P-Glycoprotein in Lipid Nanodiscs.
Biochemistry
; 60(1): 85-94, 2021 01 12.
Article
in En
| MEDLINE
| ID: mdl-33350827
ABSTRACT
P-Glycoprotein (P-gp) is an ATP-dependent efflux pump that clears a wide variety of drugs and toxins from cells. P-gp undergoes large-scale structural changes and demonstrates conformational heterogeneity even within a single catalytic or drug-bound state, although the role of heterogeneity remains unclear. P-gp is found in a variety of cell types that vary in lipid composition, which modulates its activity. An understanding of structural or dynamic changes due to the lipid environment is lacking. We aimed to determine the effects of cholesterol in a membrane on the conformational behavior of P-gp in lipid nanodiscs. The presence of cholesterol stimulates ATP hydrolysis and alters lipid order and fluidity. Hydrogen/deuterium exchange mass spectrometry demonstrates that cholesterol in the membrane induces asymmetric, long-range changes in the distributions and exchange kinetics of conformations of the nucleotide-binding domains, correlating the effects of lipid composition on activity with specific changes in the P-gp conformational landscape.
Full text:
1
Database:
MEDLINE
Main subject:
Adenosine Triphosphate
/
Cholesterol
/
ATP Binding Cassette Transporter, Subfamily B
/
Lipid Bilayers
Limits:
Animals
Language:
En
Year:
2021
Type:
Article