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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. / Jackson, Scott M; Manolaridis, Ioannis; Kowal, Julia; Zechner, Melanie; Taylor, Nicholas M.I.; Bause, Manuel; Bauer, Stefanie; Bartholomaeus, Ruben; Bernhardt, Guenther; Koenig, Burkhard; Buschauer, Armin; Stahlberg, Henning; Altmann, Karl-Heinz; Locher, Kaspar P.

In: Nature Structural and Molecular Biology, Vol. 25, No. 4, 2018, p. 333-340.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Jackson, SM, Manolaridis, I, Kowal, J, Zechner, M, Taylor, NMI, Bause, M, Bauer, S, Bartholomaeus, R, Bernhardt, G, Koenig, B, Buschauer, A, Stahlberg, H, Altmann, K-H & Locher, KP 2018, 'Structural basis of small-molecule inhibition of human multidrug transporter ABCG2', Nature Structural and Molecular Biology, vol. 25, no. 4, pp. 333-340. https://doi.org/10.1038/s41594-018-0049-1

APA

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 and Molecular Biology, 25(4), 333-340. https://doi.org/10.1038/s41594-018-0049-1

Vancouver

Jackson SM, Manolaridis I, Kowal J, Zechner M, Taylor NMI, Bause M et al. Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. Nature Structural and Molecular Biology. 2018;25(4):333-340. https://doi.org/10.1038/s41594-018-0049-1

Author

Jackson, Scott M ; Manolaridis, Ioannis ; Kowal, Julia ; Zechner, Melanie ; Taylor, Nicholas M.I. ; Bause, Manuel ; Bauer, Stefanie ; Bartholomaeus, Ruben ; Bernhardt, Guenther ; Koenig, Burkhard ; Buschauer, Armin ; Stahlberg, Henning ; Altmann, Karl-Heinz ; Locher, Kaspar P. / Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. In: Nature Structural and Molecular Biology. 2018 ; Vol. 25, No. 4. pp. 333-340.

Bibtex

@article{87812ce973ad44788b405a492a15b8d0,
title = "Structural basis of small-molecule inhibition of human multidrug transporter ABCG2",
abstract = "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.",
author = "Jackson, {Scott M} and Ioannis Manolaridis and Julia Kowal and Melanie Zechner and Taylor, {Nicholas M.I.} and Manuel Bause and Stefanie Bauer and Ruben Bartholomaeus and Guenther Bernhardt and Burkhard Koenig and Armin Buschauer and Henning Stahlberg and Karl-Heinz Altmann and Locher, {Kaspar P}",
note = "Nicholas M.I. Taylor : Present address: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark",
year = "2018",
doi = "10.1038/s41594-018-0049-1",
language = "English",
volume = "25",
pages = "333--340",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "nature publishing group",
number = "4",

}

RIS

TY - JOUR

T1 - Structural basis of small-molecule inhibition of human multidrug transporter ABCG2

AU - Jackson, Scott M

AU - Manolaridis, Ioannis

AU - Kowal, Julia

AU - Zechner, Melanie

AU - Taylor, Nicholas M.I.

AU - Bause, Manuel

AU - Bauer, Stefanie

AU - Bartholomaeus, Ruben

AU - Bernhardt, Guenther

AU - Koenig, Burkhard

AU - Buschauer, Armin

AU - Stahlberg, Henning

AU - Altmann, Karl-Heinz

AU - Locher, Kaspar P

N1 - Nicholas M.I. Taylor : Present address: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1038/s41594-018-0049-1

DO - 10.1038/s41594-018-0049-1

M3 - Journal article

C2 - 29610494

VL - 25

SP - 333

EP - 340

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

SN - 1545-9993

IS - 4

ER -

ID: 195257051