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- EMDB-47987: BSEP Apo Structure in GDN -

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Basic information

Entry
Database: EMDB / ID: EMD-47987
TitleBSEP Apo Structure in GDN
Map data
Sample
  • Cell: BSEP
    • Protein or peptide: Bile salt export pump
KeywordsBSEP / ABCB11 / MEMBRANE PROTEIN
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 / regulation of fatty acid beta-oxidation / xenobiotic export from cell / regulation of bile acid metabolic process / ABC-type bile acid transporter activity / bile acid biosynthetic process ...canalicular bile acid transmembrane transporter activity / positive regulation of bile acid secretion / Defective ABCB11 causes PFIC2 and BRIC2 / canalicular bile acid transport / intracellular canaliculus / regulation of fatty acid beta-oxidation / xenobiotic export from cell / regulation of bile acid metabolic process / ABC-type bile acid transporter activity / bile acid biosynthetic process / xenobiotic transmembrane transport / phospholipid homeostasis / bile acid metabolic process / intercellular canaliculus / bile acid transmembrane transporter activity / 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 / : / recycling endosome / transmembrane transport / response to estrogen / recycling endosome membrane / response to oxidative stress / response to ethanol / endosome / protein ubiquitination / 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: 2.8 Å
AuthorsReddy BG / Gruget C / Moore J
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Commun Biol / Year: 2025
Title: A structural and mechanistic model for BSEP dysfunction in PFIC2 cholestatic disease.
Authors: Clémence Gruget / Bharat G Reddy / Jonathan M Moore /
Abstract: BSEP (ABCB11) transports bile salts across the canalicular membrane of hepatocytes, where they are incorporated into bile. Biallelic mutations in BSEP can cause Progressive Familial Intrahepatic ...BSEP (ABCB11) transports bile salts across the canalicular membrane of hepatocytes, where they are incorporated into bile. Biallelic mutations in BSEP can cause Progressive Familial Intrahepatic Cholestasis Type 2 (PFIC2), a rare pediatric disease characterized by hepatic bile acid accumulation leading to hepatotoxicity and, ultimately, liver failure. The most frequently occurring PFIC2 disease-causing mutations are missense mutations, which often display a phenotype with decreased protein expression and impaired maturation and trafficking to the canalicular membrane. To characterize the mutational effects on protein thermodynamic stability, we carried out biophysical characterization of 13 distinct PFIC2-associated variants using in-cell thermal shift (CETSA) measurements. These experiments reveal a cluster of residues localized to the NBD2-ICL2 interface, which exhibit severe destabilization relative to wild-type BSEP. A high-resolution (2.8 Å) cryo-EM structure provides a framework for rationalizing the CETSA results, revealing a novel, NBD2-localized mechanism through which the most severe missense patient mutations drive cholestatic disease. These findings suggest potential strategies for identifying mechanism-based small molecule correctors to address BSEP trafficking defects and advance novel therapies for PFIC2 and other cholestatic diseases.
History
DepositionNov 21, 2024-
Header (metadata) releaseApr 2, 2025-
Map releaseApr 2, 2025-
UpdateJun 11, 2025-
Current statusJun 11, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47987.png

Downloads & links

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Map

FileDownload / File: emd_47987.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.8 Å/pix.
x 320 pix.
= 256.768 Å		0.8 Å/pix.
x 320 pix.
= 256.768 Å		0.8 Å/pix.
x 320 pix.
= 256.768 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8024 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.15663473 - 0.26453367
Average (Standard dev.)-0.0003608621 (±0.0063594626)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 256.768 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_47987_msk_1.map
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Half map: #2

Fileemd_47987_half_map_1.map
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Half map: #1

Fileemd_47987_half_map_2.map
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Sample components

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Entire : BSEP

EntireName: BSEP
Components
  • Cell: BSEP
    • Protein or peptide: Bile salt export pump

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Supramolecule #1: BSEP

SupramoleculeName: BSEP / type: cell / ID: 1 / Parent: 0 / Macromolecule list: all / Details: In GDN Detergent
Source (natural)Organism: Homo sapiens (human)

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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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration2 mg/mL
BufferpH: 8
GridModel: HexAuFoil / Material: GOLD / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 90 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Average electron dose: 49.13 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: EMDB MAP
EMDB ID:

31583

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 435000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

RefinementProtocol: FLEXIBLE FIT
Output model

PDB-9ege:
BSEP Apo Structure in GDN

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