Structure of the human multidrug transporter ABCG2

Research output: Contribution to journalJournal articleResearchpeer-review

ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here we present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. We visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. We observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, our results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters.

Original languageEnglish
Issue number7659
Pages (from-to)504-509
Number of pages6
Publication statusPublished - 22 Jun 2017
Externally publishedYes

    Research areas

  • ATP Binding Cassette Transporter, Sub-Family G, Member 2/antagonists & inhibitors, Adenosine Triphosphatases/chemistry, Amino Acid Sequence, Antibodies/chemistry, Binding Sites, Biological Transport, Cholesterol/chemistry, Cryoelectron Microscopy, Humans, Immunoglobulin Fab Fragments/chemistry, Models, Molecular, Neoplasm Proteins/antagonists & inhibitors, Polymorphism, Single Nucleotide/genetics, Protein Domains

ID: 194519831