Science - USA (2019-02-15)

more completely, and form a larger number of
contacts with ABCB1. This suggests that, in a
continuum of substrates and inhibitors, three-
dimensional shape complementarity and the
strength of the contacts rather than distinct bind-
ing sites are key determinants distinguishing
substrates from inhibitors. Although the func-
tional modulation of ABCB1 by cholesterol
and lipids has previously been demonstrated
( 12 , 27 – 29 ), our results illustrate specific interac-
tions and binding sites in cholesterol-containing
lipid bilayers.
Finally, given that the structures of Taxol- and
zosuquidar-bound ABCB1 reveal critical inter-
actions in a key state of the transporter, our
results may allow medicinal chemists and com-
putational biologists to exploit structural insight
into ABCB1 to guide the design of drugs or
inhibitors.

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ACKNOWLEDGMENTS

We thank the staff at the Scientific Center for Optical and

Electron Microscopy (SCOPEM) at ETH Zürich. We also

acknowledge N. Tremp for help with protein expression and

cell culture work.Funding:This work was funded by the European

Molecular Biology Organization long-term postdoctoral fellowship

to A.A., grants from the Swiss Cancer League to K.P.L., the

Swiss National Science Foundation through NCCR Structural

Biology and TransCure, the Swiss Cancer League, and U.S.

National Institutes of Health grant P20GM109091 to E.B. and

I.R.Author contributions:A.A. carried out all experimental

procedures related to protein expression and purification and

EM sample preparation. A.A. prepared cryo-EM grids and A.A.

and J.K. collected and processed EM data. E.B. and I.R. provided

UIC2-producing hybridoma cells and helped analyze data. K.P.L.

and A.A. conceived of the project and planned the experiments.

A.A. and K.P.L. wrote the manuscript with input from all

authors.Competing interests:The authors declare no competing

interests.Data and materials availability:All data are available

within the main text or supplementary materials. Cryo-EM maps

are available at the Electron Microscopy Data Bank with accession

codes EMD-4539, EMD-4540, and EMD-4541 (maps 1, 2, and

3 of Taxol-bound ABCB1, respectively) and EMD-4536 (zosuquidar-

bound ABCB1). Coordinates for deposited models are available at

the Protein Data Bank with IDs 6QEX (Taxol-bound ABCB1) and

6QEE (zosuquidar-bound ABCB1).

SUPPLEMENTARY MATERIALS

http://www.sciencemag.org/content/363/6428/753/suppl/DC1

Materials and Methods

Figs. S1 to S6

Table S1

References ( 31 – 45 )

12 October 2018; accepted 18 January 2019

10.1126/science.aav7102

Alamet al.,Science 363 , 753–756 (2019) 15 February 2019 4of4

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