8PMD

Nucleotide-bound BSEP in nanodiscs

Summary for 8PMD

• Entry DOI: 10.2210/pdb8pmd/pdb
• EMDB information: 17759
• Descriptor: Bile salt export pump, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: transport, nucleotide, nanodiscs, protein transport
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 147619.38

Authors

Liu, H.,Irobalieva, R.N.,Kowal, J.,Ni, D.,Nosol, K.,Bang-Sorensen, R.,Lancien, L.,Stahlberg, H.,Stieger, B.,Locher, K.P. (deposition date: 2023-06-28, release date: 2023-11-22)

Primary citation

Liu, H.,Irobalieva, R.N.,Kowal, J.,Ni, D.,Nosol, K.,Bang-Sorensen, R.,Lancien, L.,Stahlberg, H.,Stieger, B.,Locher, K.P.
Structural basis of bile salt extrusion and small-molecule inhibition in human BSEP.
Nat Commun, 14:7296-7296, 2023

PubMed 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 (BSEP) 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.

PubMed: 37949847
DOI: 10.1038/s41467-023-43109-1

Experimental method

ELECTRON MICROSCOPY (2.95 Å)