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Structure of the human multidrug transporter ABCG2.
- Source :
-
Nature [Nature] 2017 Jun 22; Vol. 546 (7659), pp. 504-509. Date of Electronic Publication: 2017 May 29. - Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism
Adenosine Triphosphatases chemistry
Adenosine Triphosphatases genetics
Adenosine Triphosphatases metabolism
Adenosine Triphosphatases ultrastructure
Amino Acid Sequence
Antibodies chemistry
Antibodies immunology
Antibodies ultrastructure
Binding Sites
Biological Transport
Cholesterol chemistry
Cholesterol metabolism
Humans
Immunoglobulin Fab Fragments chemistry
Immunoglobulin Fab Fragments immunology
Immunoglobulin Fab Fragments ultrastructure
Models, Molecular
Neoplasm Proteins antagonists & inhibitors
Neoplasm Proteins metabolism
Polymorphism, Single Nucleotide genetics
Protein Domains
ATP Binding Cassette Transporter, Subfamily G, Member 2 chemistry
ATP Binding Cassette Transporter, Subfamily G, Member 2 ultrastructure
Cryoelectron Microscopy
Neoplasm Proteins chemistry
Neoplasm Proteins ultrastructure
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 546
- Issue :
- 7659
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 28554189
- Full Text :
- https://doi.org/10.1038/nature22345