Transport / Inhibitor / Complex / Nanodiscs / PROTEIN TRANSPORT
機能・相同性
機能・相同性情報
canalicular bile acid transmembrane transporter activity / positive regulation of bile acid secretion / Defective ABCB11 causes PFIC2 and BRIC2 / canalicular bile acid transport / intracellular canaliculus / xenobiotic export from cell / regulation of fatty acid beta-oxidation / regulation of bile acid metabolic process / ABC-type bile acid transporter activity / bile acid transmembrane transporter activity ...canalicular bile acid transmembrane transporter activity / positive regulation of bile acid secretion / Defective ABCB11 causes PFIC2 and BRIC2 / canalicular bile acid transport / intracellular canaliculus / xenobiotic export from cell / regulation of fatty acid beta-oxidation / regulation of bile acid metabolic process / ABC-type bile acid transporter activity / bile acid transmembrane transporter activity / bile acid biosynthetic process / xenobiotic transmembrane transport / phospholipid homeostasis / intercellular canaliculus / bile acid metabolic process / bile acid and bile salt transport / ABC-type xenobiotic transporter activity / トランスロカーゼ; 他の化合物の輸送を触媒; ヌクレオシド三リン酸の加水分解に伴う / bile acid signaling pathway / lipid homeostasis / carbohydrate transmembrane transporter activity / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Recycling of bile acids and salts / xenobiotic metabolic process / fatty acid metabolic process / cholesterol homeostasis / response to organic cyclic compound / recycling endosome / transmembrane transport / response to estrogen / recycling endosome membrane / response to ethanol / response to oxidative stress / endosome / protein ubiquitination / apical plasma membrane / Golgi membrane / cell surface / ATP hydrolysis activity / extracellular exosome / ATP binding / membrane / plasma membrane 類似検索 - 分子機能
Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. ...Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性
ジャーナル: Nat Commun / 年: 2023 タイトル: Structural basis of bile salt extrusion and small-molecule inhibition in human BSEP. 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 / 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.