Structural basis of small-molecule inhibition of human multidrug transporter ABCG2

Jackson, Scott M. and Manolaridis, Ioannis and Kowal, Julia and Zechner, Melanie and Taylor, Nicholas M. I. and Bause, Manuel and Bauer, Stefanie and Bartholomaeus, Ruben and Bernhardt, Guenther and Koenig, Burkhard and Buschauer, Armin and Stahlberg, Henning and Altmann, Karl-Heinz and Locher, Kaspar P.. (2018) Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. Nature structural & molecular biology, 25 (4). pp. 333-340.

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Official URL: https://edoc.unibas.ch/64182/

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ABCG2 is an ATP-binding cassette (ABC) transporter that protects tissues against xenobiotics, affects the pharmacokinetics of drugs and contributes to multidrug resistance. Although many inhibitors and modulators of ABCG2 have been developed, understanding their structure-activity relationship requires high-resolution structural insight. Here, we present cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar. Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking access for substrates and preventing conformational changes required for ATP hydrolysis. The high resolutions allowed for de novo building of the entire transporter and also revealed tightly bound phospholipids and cholesterol interacting with the lipid-exposed surface of the transmembrane domains (TMDs). Extensive chemical modifications of the Ko143 scaffold combined with in vitro functional analyses revealed the details of ABCG2 interactions with this compound family and provide a basis for the design of novel inhibitors and modulators.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Structural Biology (Stahlberg)
UniBasel Contributors:Stahlberg, Henning
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:27 Apr 2020 10:44
Deposited On:27 Apr 2020 10:44

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