Titre
Structure of the human multidrug transporter ABCG2.
Type
article
Institution
Externe
Périodique
Auteur(s)
Taylor, NMI
Auteure/Auteur
Manolaridis, I.
Auteure/Auteur
Jackson, S.M.
Auteure/Auteur
Kowal, J.
Auteure/Auteur
Stahlberg, H.
Auteure/Auteur
Locher, K.P.
Auteure/Auteur
Liens vers les personnes
ISSN
1476-4687
Statut éditorial
Publié
Date de publication
2017-06-22
Volume
546
Numéro
7659
Première page
504
Dernière page/numéro d’article
509
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Sujets
PID Serval
serval:BIB_6507C918A284
PMID
Date de création
2023-06-09T14:02:37.111Z
Date de création dans IRIS
2025-05-20T20:53:44Z