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3.A.1.201.2
Bile salt export pump, BSEP, ABCB11 or SPGP in the canalicular membrane of liver cells, is associated with progressive familial intrahepatic cholestasis-2 and benign recurrent intrahepatic cholestasis (Kagawa et al., 2008; Stindt et al. 2013; Park et al. 2016). It exports unconjugaged bile salts and glycine conjugates > taurine conjugates as well as the statin, pravastatin (Nigam 2015). BSEP mediates biliary excretion of bile acids from hepatocytes. Compounds based on GW4064 (Q96RI1), a representative farnesoid X receptor (RXR) agonist, enhance E297G BSEP transport activity (Misawa et al., 2012). Rescue of bile acid transport by ABCB11 variants by CFTR potentiators has been extensively documented as a possible treatment for progressive familial intrahepatic cholestasis-2 (Mareux et al. 2022).  BSEP 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. Liu et al. 2023 reported 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. Two high-resolution structures of BSEP trapped in distinct nucleotide-bound states by using a catalytically inactivated BSEP variant (BSEP(E1244Q)) to visualize a pre-hydrolysis state, and wild-type BSEP trapped by vanadate to visualize a post-hydrolysis state. These 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 (Liu et al. 2023).

Accession Number:O95342
Protein Name:AB11 aka BSEP aka SPGP aka ABCB11
Length:1321
Molecular Weight:146407.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:12
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate bile acid taurine conjugate, bile acid salt, bile acid glycine conjugate, bile acid

Cross database links:

RefSeq: NP_003733.2   
Entrez Gene ID: 8647   
Pfam: PF00664    PF00005   
OMIM: 601847  phenotype
603201  gene
605479  phenotype
KEGG: hsa:8647   

Gene Ontology

GO:0005887 C:integral to plasma membrane
GO:0005624 C:membrane fraction
GO:0005524 F:ATP binding
GO:0015432 F:bile acid-exporting ATPase activity
GO:0008554 F:sodium-exporting ATPase activity, phosphory...
GO:0055085 P:transmembrane transport

References (11)

[1] “A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.”  Strautnieks S.S.et.al.   9806540
[2] “Generation and annotation of the DNA sequences of human chromosomes 2 and 4.”  Hillier L.W.et.al.   15815621
[3] “Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.”  Jansen P.L.M.et.al.   10579978
[4] “Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population.”  Saito S.et.al.   11829140
[5] “FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels.”  Chen H.-L.et.al.   11815775
[6] “Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11.”  van Mil S.W.C.et.al.   15300568
[7] “Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.”  Pauli-Magnus C.et.al.   15077010
[8] “Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis.”  Noe J.et.al.   16039748
[9] “Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).”  Lang T.et.al.   16763017
[10] “Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver.”  Meier Y.et.al.   16799996
[11] “Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.”  Lang C.et.al.   17264802
Structure:
6LR0     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MSDSVILRSI KKFGEENDGF ESDKSYNNDK KSRLQDEKKG DGVRVGFFQL FRFSSSTDIW 
61:	LMFVGSLCAF LHGIAQPGVL LIFGTMTDVF IDYDVELQEL QIPGKACVNN TIVWTNSSLN 
121:	QNMTNGTRCG LLNIESEMIK FASYYAGIAV AVLITGYIQI CFWVIAAARQ IQKMRKFYFR 
181:	RIMRMEIGWF DCNSVGELNT RFSDDINKIN DAIADQMALF IQRMTSTICG FLLGFFRGWK 
241:	LTLVIISVSP LIGIGAATIG LSVSKFTDYE LKAYAKAGVV ADEVISSMRT VAAFGGEKRE 
301:	VERYEKNLVF AQRWGIRKGI VMGFFTGFVW CLIFLCYALA FWYGSTLVLD EGEYTPGTLV 
361:	QIFLSVIVGA LNLGNASPCL EAFATGRAAA TSIFETIDRK PIIDCMSEDG YKLDRIKGEI 
421:	EFHNVTFHYP SRPEVKILND LNMVIKPGEM TALVGPSGAG KSTALQLIQR FYDPCEGMVT 
481:	VDGHDIRSLN IQWLRDQIGI VEQEPVLFST TIAENIRYGR EDATMEDIVQ AAKEANAYNF 
541:	IMDLPQQFDT LVGEGGGQMS GGQKQRVAIA RALIRNPKIL LLDMATSALD NESEAMVQEV 
601:	LSKIQHGHTI ISVAHRLSTV RAADTIIGFE HGTAVERGTH EELLERKGVY FTLVTLQSQG 
661:	NQALNEEDIK DATEDDMLAR TFSRGSYQDS LRASIRQRSK SQLSYLVHEP PLAVVDHKST 
721:	YEEDRKDKDI PVQEEVEPAP VRRILKFSAP EWPYMLVGSV GAAVNGTVTP LYAFLFSQIL 
781:	GTFSIPDKEE QRSQINGVCL LFVAMGCVSL FTQFLQGYAF AKSGELLTKR LRKFGFRAML 
841:	GQDIAWFDDL RNSPGALTTR LATDASQVQG AAGSQIGMIV NSFTNVTVAM IIAFSFSWKL 
901:	SLVILCFFPF LALSGATQTR MLTGFASRDK QALEMVGQIT NEALSNIRTV AGIGKERRFI 
961:	EALETELEKP FKTAIQKANI YGFCFAFAQC IMFIANSASY RYGGYLISNE GLHFSYVFRV 
1021:	ISAVVLSATA LGRAFSYTPS YAKAKISAAR FFQLLDRQPP ISVYNTAGEK WDNFQGKIDF 
1081:	VDCKFTYPSR PDSQVLNGLS VSISPGQTLA FVGSSGCGKS TSIQLLERFY DPDQGKVMID 
1141:	GHDSKKVNVQ FLRSNIGIVS QEPVLFACSI MDNIKYGDNT KEIPMERVIA AAKQAQLHDF 
1201:	VMSLPEKYET NVGSQGSQLS RGEKQRIAIA RAIVRDPKIL LLDEATSALD TESEKTVQVA 
1261:	LDKAREGRTC IVIAHRLSTI QNADIIAVMA QGVVIEKGTH EELMAQKGAY YKLVTTGSPI 
1321:	S