Cryo-EM Analysis of the Conformational Landscape of Human P-glycoprotein (ABCB1) During its Catalytic Cycle.

Journal Article (Journal Article)

The multidrug transporter P-glycoprotein (P-gp, ABCB1) is an ATP-dependent 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 conducted with P-gp and its orthologs, or from structures of other ATP-binding cassette 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.

Full Text

Duke Authors

Cited Authors

  • Frank, GA; Shukla, S; Rao, P; Borgnia, MJ; Bartesaghi, A; Merk, A; Mobin, A; Esser, L; Earl, LA; Gottesman, MM; Xia, D; Ambudkar, SV; Subramaniam, S

Published Date

  • July 2016

Published In

Volume / Issue

  • 90 / 1

Start / End Page

  • 35 - 41

PubMed ID

  • 27190212

Pubmed Central ID

  • PMC4931865

Electronic International Standard Serial Number (EISSN)

  • 1521-0111

Digital Object Identifier (DOI)

  • 10.1124/mol.116.104190


  • eng

Conference Location

  • United States