RT Journal Article
SR Electronic
T1 Cryo-EM analysis of the conformational landscape of human P-glycoprotein (ABCB1) during its catalytic cycle
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.116.104190
DO 10.1124/mol.116.104190
A1 Gabriel Frank
A1 Suneet Shukla
A1 Prashant Rao
A1 Mario J Borgnia
A1 Alberto Bartesaghi
A1 Alan Merk
A1 Aerfa Mobin
A1 Lothar Esser
A1 Lesley A. Earl
A1 Michael M Gottesman
A1 Di Xia
A1 Suresh V. Ambudkar
A1 Sriram Subramaniam
YR 2016
UL http://molpharm.aspetjournals.org/content/early/2016/05/11/mol.116.104190.abstract
AB The multidrug transporter P-glycoprotein (P-gp, ABCB1) is an ATP-dependent efflux pump that mediates the efflux of structurally diverse drugs and xenobiotics across cell membranes, affecting drug pharmacokinetics and contributing to the development of multidrug resistance. Structural information about the conformational changes in human P-gp during the ATP hydrolysis cycle has not been directly demonstrated, although mechanistic information has been inferred from biochemical and biophysical studies done with P-gp and its orthologs, or from structures of other ABC transporters. Using single particle cryo-electron microscopy, we report the surprising discovery that, in the absence of the transport substrate and nucleotides, human P-gp can exist in both open (nucleotide-binding-domains (NBDs) apart; inward-facing) and closed (NBDs close; outward-facing) conformations. We also probe conformational states of human P-gp during the catalytic cycle, and demonstrate that following ATP hydrolysis, P-gp transitions through a complete closed conformation to a complete open conformation in the presence of ADP.