Cryo-EM analysis of the conformational landscape of human P-glycoprotein (ABCB1) during its catalytic cycle

Gabriel Frank, Suneet Shukla, Prashant Rao, Mario J. Borgnia, Alberto Bartesaghi, Alan Merk, Aerfa Mobin, Lothar Esser, Lesley A. Earl, Michael M. Gottesman, Di Xia, Suresh V. Ambudkar, Sriram Subramaniam

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


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; inwardfacing] 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.

Original languageEnglish
Pages (from-to)35-41
Number of pages7
JournalMolecular Pharmacology
Issue number1
StatePublished - 1 Jul 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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