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- EMDB-17758: Human bile salt export pump (BSEP) in complex with inhibitor GBM ... -

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Basic information

Entry
Database: EMDB / ID: EMD-17758
TitleHuman bile salt export pump (BSEP) in complex with inhibitor GBM in nanodiscs
Map data
Sample
  • Complex: The complex of BSEP with inhibitor GBM
    • Protein or peptide: Bile salt export pump
  • Ligand: CHOLESTEROL
  • Ligand: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide
KeywordsTransport / Inhibitor / Complex / Nanodiscs / PROTEIN TRANSPORT
Function / homology
Function and homology information


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 / ABC-type bile acid transporter activity / regulation of bile acid metabolic process / 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 / ABC-type bile acid transporter activity / regulation of bile acid metabolic process / bile acid transmembrane transporter activity / ABC-type oligopeptide transporter activity / xenobiotic transmembrane transport / bile acid biosynthetic process / phospholipid homeostasis / intercellular canaliculus / bile acid metabolic process / bile acid and bile salt transport / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / ABC-type xenobiotic transporter activity / 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 / protein ubiquitination / endosome / apical plasma membrane / Golgi membrane / cell surface / ATP hydrolysis activity / extracellular exosome / ATP binding / plasma membrane
Similarity search - Function
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
Similarity search - Domain/homology
Bile salt export pump
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.22 Å
AuthorsLiu H / Irobalieva RN / Kowal J / Ni D / Nosol K / Bang-Sorensen R / Lancien L / Stahlberg H / Stieger B / Locher KP
Funding support Switzerland, 3 items
OrganizationGrant numberCountry
Swiss National Science Foundation189111 Switzerland
Swiss National Science Foundation206089 Switzerland
Swiss National Science Foundation185544 Switzerland
CitationJournal: Nat Commun / Year: 2023
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
DepositionJun 28, 2023-
Header (metadata) releaseNov 22, 2023-
Map releaseNov 22, 2023-
UpdateNov 22, 2023-
Current statusNov 22, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17758.png

Downloads & links

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Map

FileDownload / File: emd_17758.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.726 Å
Density
Contour LevelBy AUTHOR: 0.00558
Minimum - Maximum-0.024990631 - 0.03720959
Average (Standard dev.)-0.000036793244 (±0.00080681284)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 261.36002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_17758_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_17758_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_17758_half_map_2.map
Projections & Slices
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Sample components

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Entire : The complex of BSEP with inhibitor GBM

EntireName: The complex of BSEP with inhibitor GBM
Components
  • Complex: The complex of BSEP with inhibitor GBM
    • Protein or peptide: Bile salt export pump
  • Ligand: CHOLESTEROL
  • Ligand: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide

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Supramolecule #1: The complex of BSEP with inhibitor GBM

SupramoleculeName: The complex of BSEP with inhibitor GBM / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 146 KDa

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Macromolecule #1: Bile salt export pump

MacromoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 146.557391 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #2: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 2 / Number of copies: 8 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #3: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-...

MacromoleculeName: 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide
type: ligand / ID: 3 / Number of copies: 1 / Formula: GBM
Molecular weightTheoretical: 494.004 Da
Chemical component information

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

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6lr0

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 173511
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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