Structural basis of bile salt extrusion and small-molecule inhibition in human BSEP

Hongtao Liu, Rossitza N. Irobalieva, Julia Kowal, Dongchun Ni, Kamil Nosol, Rose Bang-Sørensen, Loïck Lancien, Henning Stahlberg, Bruno Stieger and Kaspar P. Locher ()
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Hongtao Liu: ETH Zürich
Rossitza N. Irobalieva: ETH Zürich
Julia Kowal: ETH Zürich
Dongchun Ni: University of Lausanne
Kamil Nosol: ETH Zürich
Rose Bang-Sørensen: ETH Zürich
Loïck Lancien: ETH Zürich
Henning Stahlberg: University of Lausanne
Bruno Stieger: ETH Zürich
Kaspar P. Locher: ETH Zürich

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract BSEP (ABCB11) is an ATP-binding cassette transporter that is expressed in hepatocytes and extrudes bile salts into the canaliculi of the liver. BSEP dysfunction, caused by mutations or induced by drugs, is frequently associated with severe cholestatic liver disease. We report the cryo-EM structure of glibenclamide-bound human BSEP in nanodiscs, revealing the basis of small-molecule inhibition. Glibenclamide binds the apex of a central binding pocket between the transmembrane domains, preventing BSEP from undergoing conformational changes, and thus rationalizing the reduced uptake of bile salts. We further report two high-resolution structures of BSEP trapped in distinct nucleotide-bound states by using a catalytically inactivated BSEP variant (BSEPE1244Q) to visualize a pre-hydrolysis state, and wild-type BSEP trapped by vanadate to visualize a post-hydrolysis state. Our studies provide structural and functional insight into the mechanism of bile salt extrusion and into small-molecule inhibition of BSEP, which may rationalize drug-induced liver toxicity.

Date: 2023
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DOI: 10.1038/s41467-023-43109-1

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