EMD-17761

Single-particle
2.81 Å
EMD-17761 Deposition: 28/06/2023
Map released: 29/11/2023
Last modified: 29/11/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-17761

Vanadate-trapped BSEP in nanodiscs

EMD-17761

Single-particle
2.81 Å
EMD-17761 Deposition: 28/06/2023
Map released: 29/11/2023
Last modified: 29/11/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Vanadate-trapped BSEP in nanodiscs
Fitted models: 8pmj (Avg. Q-score: 0.59)

Deposition Authors: Liu H , Irobalieva RN , Kowal J , Ni D , Nosol K , Bang-Sorensen R , Lancien L, Stahlberg H , Stieger B , Locher KP
Structural basis of bile salt extrusion and small-molecule inhibition in human BSEP.
Liu H , Irobalieva RN , Kowal J , Ni D , Nosol K , Bang-Sorensen R , Lancien L, Stahlberg H , Stieger B , Locher KP
(2023) Nat Commun , 14 , 7296 - 7296
PUBMED: 37949847
DOI: doi:10.1038/s41467-023-43109-1
ISSN: 2041-1723
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.