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- EMDB-17759: Nucleotide-bound BSEP in nanodiscs -

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Basic information

Entry
Database: EMDB / ID: EMD-17759
TitleNucleotide-bound BSEP in nanodiscs
Map data
Sample
  • Complex: Nucleotide-bound BSEP in nanodiscs
    • Protein or peptide: Bile salt export pump
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: water
KeywordsTransport / Nucleotide / 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 / regulation of bile acid metabolic process / ABC-type bile acid transporter activity / bile acid signaling pathway ...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 signaling pathway / bile acid biosynthetic process / xenobiotic transmembrane transport / bile acid transmembrane transporter activity / phospholipid homeostasis / intercellular canaliculus / bile acid metabolic process / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / ABC-type xenobiotic transporter activity / bile acid and bile salt transport / 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 / cholesterol homeostasis / fatty acid metabolic process / 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
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: 2.95 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_17759.png

Downloads & links

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Map

FileDownload / File: emd_17759.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 384 pix.
= 253.44 Å		0.66 Å/pix.
x 384 pix.
= 253.44 Å		0.66 Å/pix.
x 384 pix.
= 253.44 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.66 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0181
Minimum - Maximum-0.07799269 - 0.13417196
Average (Standard dev.)0.000006322539 (±0.0032984312)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 253.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_17759_msk_1.map
Projections & Slices
AxesZYX

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Histogram

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Half map: #2

Fileemd_17759_half_map_1.map
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Half map: #1

Fileemd_17759_half_map_2.map
Projections & Slices
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Sample components

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Entire : Nucleotide-bound BSEP in nanodiscs

EntireName: Nucleotide-bound BSEP in nanodiscs
Components
  • Complex: Nucleotide-bound BSEP in nanodiscs
    • Protein or peptide: Bile salt export pump
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: water

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Supramolecule #1: Nucleotide-bound BSEP in nanodiscs

SupramoleculeName: Nucleotide-bound BSEP in nanodiscs / 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: 146.556406 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 DPKILLLDQA TSALDTESEK TVQVALDKAR EGRTCIVIAH RLSTI QNAD IIAVMAQGVV IEKGTHEELM AQKGAYYKLV TTGSPIS

UniProtKB: Bile salt export pump

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 48.0 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: 2.4 µm / Nominal defocus min: 0.6 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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 126524
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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