The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Structural basis of small-molecule inhibition of human multidrug transporter ABCG2
Open accessAbstract
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. Cryo-EM structures of human ABCG2 bound to synthetic derivatives of inhibitor Ko143 or the multidrug resistance modulator tariquidar together with insight into the structure–activity relationship of the Ko143 scaffold provide a basis for the design of novel ABCG2 inhibitors.
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Multidrug resistance in cancer: role of ATP–dependent transporters
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The Inhibitor Ko143 Is Not Specific for ABCG2
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Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies
Catalano, A., Iacopetta, D., Ceramella, J., Scumaci, D., Giuzio, F., Saturnino, C., Aquaro, S., Rosano, C., & Sinicropi, M. S. (2022) · Molecules · doi:10.3390/molecules27030616 · Cited by 450
Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states
Manolaridis, I., Jackson, S. M., Taylor, N. M. I., Kowal, J., Stahlberg, H., & Locher, K. P. (2018) · Nature · doi:10.1038/s41586-018-0680-3 · Cited by 228
Self-citationABCG2 transports anticancer drugs via a closed-to-open switch
Orlando, B. J., & Liao, M. (2020) · Nature Communications · doi:10.1038/s41467-020-16155-2 · Cited by 198
Plummer, A. M., Culbertson, A. T., & Liao, M. (2021) · Annual Review of Physiology · doi:10.1146/annurev-physiol-031620-094944 · Cited by 60
Metadata
- Authors
- Jackson, S. M., Manolaridis, I., Kowal, J., Zechner, M., Taylor, N. M. I., Bause, M., Bauer, S., Bartholomaeus, R., Bernhardt, G., Koenig, B., Buschauer, A., Stahlberg, H., Altmann, K.-H., & Locher, K. P.
- Venue
- Nature Structural & Molecular Biology
- Published
- 2018-04
- Volume
- 25
- Issue
- 4
- Pages
- 333-340
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2796451806
- Cited by
- 321
- References
- 8
- FWCI
- 14.16
- Type
- journal article
- Language
- en
- Open access
- green
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- Jackson, S. M., Manolaridis, I., Kowal, J., Zechner, M., Taylor, N. M. I., Bause, M., Bauer, S., Bartholomaeus, R., Bernhardt, G., Koenig, B., Buschauer, A., Stahlberg, H., Altmann, K.-H., & Locher, K. P. (2018). Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. Nature Structural & Molecular Biology. https://doi.org/10.1038/s41594-018-0049-1
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