+検索条件
-Structure paper
タイトル | Structural basis of bile salt extrusion and small-molecule inhibition in human BSEP. |
---|---|
ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 7296, Year 2023 |
掲載日 | 2023年11月10日 |
著者 | Hongtao Liu / Rossitza N Irobalieva / Julia Kowal / Dongchun Ni / Kamil Nosol / Rose Bang-Sørensen / Loïck Lancien / Henning Stahlberg / Bruno Stieger / Kaspar P Locher / |
PubMed 要旨 | 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 ...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. |
リンク | Nat Commun / PubMed:37949847 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.81 - 3.22 Å |
構造データ | EMDB-17758, PDB-8pm6: EMDB-17759, PDB-8pmd: EMDB-17761, PDB-8pmj: |
化合物 | ChemComp-CLR: ChemComp-GBM: ChemComp-ATP: ChemComp-MG: ChemComp-HOH: ChemComp-ADP: ChemComp-VO4: |
由来 |
|
キーワード | PROTEIN TRANSPORT / Transport / Inhibitor / Complex / Nanodiscs / Nucleotide / Vanadate |