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- EMDB-17758: Human bile salt export pump (BSEP) in complex with inhibitor GBM ... -
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Open data
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Basic information
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Title | Human bile salt export pump (BSEP) in complex with inhibitor GBM in nanodiscs | ||||||||||||
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![]() | Transport / Inhibitor / Complex / Nanodiscs / PROTEIN TRANSPORT | ||||||||||||
Function / homology | ![]() 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 / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / 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 Similarity search - Function | ||||||||||||
Biological species | ![]() | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.22 Å | ||||||||||||
![]() | Liu H / Irobalieva RN / Kowal J / Ni D / Nosol K / Bang-Sorensen R / Lancien L / Stahlberg H / Stieger B / Locher KP | ||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis of bile salt extrusion and small-molecule inhibition in human BSEP. Authors: Hongtao Liu / Rossitza N Irobalieva / Julia Kowal / Dongchun Ni / Kamil Nosol / Rose Bang-Sørensen / Loïck Lancien / Henning Stahlberg / Bruno Stieger / Kaspar P Locher / ![]() 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 ...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. | ||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 165 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 16.6 KB 16.6 KB | Display Display | ![]() |
Images | ![]() | 89.8 KB | ||
Masks | ![]() | 178 MB | ![]() | |
Filedesc metadata | ![]() | 6.5 KB | ||
Others | ![]() ![]() | 141.4 MB 141.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8pm6MC ![]() 8pmdC ![]() 8pmjC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.726 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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-Half map: #2
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Density Histograms |
-Half map: #1
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Density Histograms |
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Sample components
-Entire : The complex of BSEP with inhibitor GBM
Entire | Name: The complex of BSEP with inhibitor GBM |
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Components |
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-Supramolecule #1: The complex of BSEP with inhibitor GBM
Supramolecule | Name: The complex of BSEP with inhibitor GBM / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 146 KDa |
-Macromolecule #1: Bile salt export pump
Macromolecule | Name: Bile salt export pump / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO EC number: Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 146.557391 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MSDSVILRSI KKFGEENDGF ESDKSYNNDK KSRLQDEKKG DGVRVGFFQL FRFSSSTDIW LMFVGSLCAF LHGIAQPGVL LIFGTMTDV FIDYDVELQE LQIPGKACVN NTIVWTNSSL NQNMTNGTRC GLLNIESEMI KFASYYAGIA VAVLITGYIQ I CFWVIAAA ...String: MSDSVILRSI KKFGEENDGF ESDKSYNNDK KSRLQDEKKG DGVRVGFFQL FRFSSSTDIW LMFVGSLCAF LHGIAQPGVL LIFGTMTDV FIDYDVELQE LQIPGKACVN NTIVWTNSSL NQNMTNGTRC GLLNIESEMI KFASYYAGIA VAVLITGYIQ I CFWVIAAA RQIQKMRKFY FRRIMRMEIG WFDCNSVGEL NTRFSDDINK INDAIADQMA LFIQRMTSTI CGFLLGFFRG WK LTLVIIS VSPLIGIGAA TIGLSVSKFT DYELKAYAKA GVVADEVISS MRTVAAFGGE KREVERYEKN LVFAQRWGIR KGI VMGFFT GFVWCLIFLC YALAFWYGST LVLDEGEYTP GTLVQIFLSV IVGALNLGNA SPCLEAFATG RAAATSIFET IDRK PIIDC MSEDGYKLDR IKGEIEFHNV TFHYPSRPEV KILNDLNMVI KPGEMTALVG PSGAGKSTAL QLIQRFYDPC EGMVT VDGH DIRSLNIQWL RDQIGIVEQE PVLFSTTIAE NIRYGREDAT MEDIVQAAKE ANAYNFIMDL PQQFDTLVGE GGGQMS GGQ KQRVAIARAL IRNPKILLLD MATSALDNES EAMVQEVLSK IQHGHTIISV AHRLSTVRAA DTIIGFEHGT AVERGTH EE LLERKGVYFT LVTLQSQGNQ ALNEEDIKDA TEDDMLARTF SRGSYQDSLR ASIRQRSKSQ LSYLVHEPPL AVVDHKST Y EEDRKDKDIP VQEEVEPAPV RRILKFSAPE WPYMLVGSVG AAVNGTVTPL YAFLFSQILG TFSIPDKEEQ RSQINGVCL LFVAMGCVSL FTQFLQGYAF AKSGELLTKR LRKFGFRAML GQDIAWFDDL RNSPGALTTR LATDASQVQG AAGSQIGMIV NSFTNVTVA MIIAFSFSWK LSLVILCFFP FLALSGATQT RMLTGFASRD KQALEMVGQI TNEALSNIRT VAGIGKERRF I EALETELE KPFKTAIQKA NIYGFCFAFA QCIMFIANSA SYRYGGYLIS NEGLHFSYVF RVISAVVLSA TALGRAFSYT PS YAKAKIS AARFFQLLDR QPPISVYNTA GEKWDNFQGK IDFVDCKFTY PSRPDSQVLN GLSVSISPGQ TLAFVGSSGC GKS TSIQLL ERFYDPDQGK VMIDGHDSKK VNVQFLRSNI GIVSQEPVLF ACSIMDNIKY GDNTKEIPME RVIAAAKQAQ LHDF VMSLP EKYETNVGSQ GSQLSRGEKQ RIAIARAIVR DPKILLLDEA TSALDTESEK TVQVALDKAR EGRTCIVIAH RLSTI QNAD IIAVMAQGVV IEKGTHEELM AQKGAYYKLV TTGSPIS UniProtKB: Bile salt export pump |
-Macromolecule #2: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 2 / Number of copies: 8 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ![]() ChemComp-CLR: |
-Macromolecule #3: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-...
Macromolecule | Name: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide type: ligand / ID: 3 / Number of copies: 1 / Formula: GBM |
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Molecular weight | Theoretical: 494.004 Da |
Chemical component information | ![]() ChemComp-GBM: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE-PROPANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 173511 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |