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- PDB-9ege: BSEP Apo Structure in GDN -

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Entry
Database: PDB / ID: 9ege
TitleBSEP Apo Structure in GDN
ComponentsBile salt export pump
KeywordsMEMBRANE PROTEIN / BSEP / ABCB11
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 / intercellular canaliculus / bile acid metabolic process / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsReddy, B.G. / Gruget, C. / Moore, J.
Funding support1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bile salt export pump


Theoretical massNumber of molelcules
Total (without water)146,5571
Polymers146,5571
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Bile salt export pump / ATP-binding cassette sub-family B member 11


Mass: 146557.391 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB11, BSEP / Production host: Homo sapiens (human)
References: UniProt: O95342, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: BSEP / Type: CELL / Details: In GDN Detergent / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: HexAuFoil
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Image recordingElectron dose: 49.13 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 435000 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049762
ELECTRON MICROSCOPYf_angle_d0.52113201
ELECTRON MICROSCOPYf_dihedral_angle_d4.7721330
ELECTRON MICROSCOPYf_chiral_restr0.0391502
ELECTRON MICROSCOPYf_plane_restr0.0041690

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