TY - JOUR
T1 - Structure of the human multidrug transporter ABCG2
AU - Taylor, Nicholas M I
AU - Manolaridis, Ioannis
AU - Jackson, Scott M
AU - Kowal, Julia
AU - Stahlberg, Henning
AU - Locher, Kaspar P
PY - 2017/6/22
Y1 - 2017/6/22
N2 - 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.
AB - 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.
KW - ATP Binding Cassette Transporter, Sub-Family G, Member 2/antagonists & inhibitors
KW - Adenosine Triphosphatases/chemistry
KW - Amino Acid Sequence
KW - Antibodies/chemistry
KW - Binding Sites
KW - Biological Transport
KW - Cholesterol/chemistry
KW - Cryoelectron Microscopy
KW - Humans
KW - Immunoglobulin Fab Fragments/chemistry
KW - Models, Molecular
KW - Neoplasm Proteins/antagonists & inhibitors
KW - Polymorphism, Single Nucleotide/genetics
KW - Protein Domains
U2 - 10.1038/nature22345
DO - 10.1038/nature22345
M3 - Journal article
C2 - 28554189
SN - 0028-0836
VL - 546
SP - 504
EP - 509
JO - Nature
JF - Nature
IS - 7659
ER -
