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- PDB-8pm6: Human bile salt export pump (BSEP) in complex with inhibitor GBM ... -

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Basic information

Entry
Database: PDB / ID: 8pm6
TitleHuman bile salt export pump (BSEP) in complex with inhibitor GBM in nanodiscs
ComponentsBile salt export pump
KeywordsPROTEIN TRANSPORT / Transport / Inhibitor / Complex / Nanodiscs
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 / bile acid biosynthetic process / xenobiotic transmembrane transport / 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 / cholesterol homeostasis / fatty acid metabolic process / transmembrane transport / response to organic cyclic compound / recycling endosome / 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
CHOLESTEROL / Chem-GBM / Bile salt export pump
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.22 Å
AuthorsLiu, H. / Irobalieva, R.N. / Kowal, J. / Ni, D. / Nosol, K. / Bang-Sorensen, R. / Lancien, L. / Stahlberg, H. / Stieger, B. / Locher, K.P.
Funding support Switzerland, 3items
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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 22, 2023Provider: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,14510
Polymers146,5571
Non-polymers3,5879
Water0
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
#2: Chemical
ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C27H46O
#3: Chemical ChemComp-GBM / 5-chloro-N-(2-{4-[(cyclohexylcarbamoyl)sulfamoyl]phenyl}ethyl)-2-methoxybenzamide / Glibenclamide / Glyburide / Glibenclamide


Mass: 494.004 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28ClN3O5S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
Has ligand of interestY

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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: The complex of BSEP with inhibitor GBM / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.146 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 173511 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0067946
ELECTRON MICROSCOPYf_angle_d0.65510829
ELECTRON MICROSCOPYf_dihedral_angle_d10.2011416
ELECTRON MICROSCOPYf_chiral_restr0.0411262
ELECTRON MICROSCOPYf_plane_restr0.0061295

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