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Structure paper

TitleStructural basis of bile salt extrusion and small-molecule inhibition in human BSEP.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 7296, Year 2023
Publish dateNov 10, 2023
AuthorsHongtao Liu / Rossitza N Irobalieva / Julia Kowal / Dongchun Ni / Kamil Nosol / Rose Bang-Sørensen / Loïck Lancien / Henning Stahlberg / Bruno Stieger / Kaspar P Locher /
PubMed AbstractBSEP (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 ...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.
External linksNat Commun / PubMed:37949847 / PubMed Central
MethodsEM (single particle)
Resolution2.81 - 3.22 Å
Structure data

17758

8pm6

EMDB-17758, PDB-8pm6:
Human bile salt export pump (BSEP) in complex with inhibitor GBM in nanodiscs
Method: EM (single particle) / Resolution: 3.22 Å

17759

8pmd

EMDB-17759, PDB-8pmd:
Nucleotide-bound BSEP in nanodiscs
Method: EM (single particle) / Resolution: 2.95 Å

17761

8pmj

EMDB-17761, PDB-8pmj:
Vanadate-trapped BSEP in nanodiscs
Method: EM (single particle) / Resolution: 2.81 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-GBM:
5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide / medication*YM / Glibenclamide

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER / Water

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

ChemComp-VO4:
VANADATE ION / Vanadate

Source
  • homo sapiens (human)
KeywordsPROTEIN TRANSPORT / Transport / Inhibitor / Complex / Nanodiscs / Nucleotide / Vanadate

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