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- PDB-6s7p: Nucleotide bound ABCB4 -

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Basic information

Entry
Database: PDB / ID: 6s7p
TitleNucleotide bound ABCB4
ComponentsPhosphatidylcholine translocator ABCB4
KeywordsTRANSPORT PROTEIN / ABC Transporter / Lipid extruder
Function / homology
Function and homology information


response to fenofibrate / Defective ABCB4 causes PFIC3, ICP3 and GBD1 / positive regulation of phospholipid transport / positive regulation of phospholipid translocation / bile acid secretion / phospholipid transporter activity / cellular response to bile acid / phosphatidylcholine floppase activity / intercellular canaliculus / P-type phospholipid transporter ...response to fenofibrate / Defective ABCB4 causes PFIC3, ICP3 and GBD1 / positive regulation of phospholipid transport / positive regulation of phospholipid translocation / bile acid secretion / phospholipid transporter activity / cellular response to bile acid / phosphatidylcholine floppase activity / intercellular canaliculus / P-type phospholipid transporter / positive regulation of cholesterol transport / phospholipid translocation / clathrin-coated vesicle / lipid homeostasis / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / ABC-family proteins mediated transport / PPARA activates gene expression / lipid metabolic process / transmembrane transport / membrane raft / apical plasma membrane / focal adhesion / ATP hydrolysis activity / extracellular exosome / nucleoplasm / ATP binding / membrane / plasma membrane / cytosol / cytoplasm
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
ADENOSINE-5'-TRIPHOSPHATE / CHOLESTEROL / Phosphatidylcholine translocator ABCB4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsOlsen, J.A. / Alam, A. / Kowal, J. / Stieger, B. / Locher, K.P.
Funding support Denmark, 1items
OrganizationGrant numberCountry
Danish Council for Independent ResearchDFF-4181-00021 Denmark
CitationJournal: Nat Struct Mol Biol / Year: 2020
Title: Structure of the human lipid exporter ABCB4 in a lipid environment.
Authors: Jeppe A Olsen / Amer Alam / Julia Kowal / Bruno Stieger / Kaspar P Locher /
Abstract: ABCB4 is an ATP-binding cassette transporter that extrudes phosphatidylcholine into the bile canaliculi of the liver. Its dysfunction or inhibition by drugs can cause severe, chronic liver disease or ...ABCB4 is an ATP-binding cassette transporter that extrudes phosphatidylcholine into the bile canaliculi of the liver. Its dysfunction or inhibition by drugs can cause severe, chronic liver disease or drug-induced liver injury. We determined the cryo-EM structure of nanodisc-reconstituted human ABCB4 trapped in an ATP-bound state at a resolution of 3.2 Å. The nucleotide binding domains form a closed conformation containing two bound ATP molecules, but only one of the ATPase sites contains bound Mg. The transmembrane domains adopt a collapsed conformation at the level of the lipid bilayer, but we observed a large, hydrophilic and fully occluded cavity at the level of the cytoplasmic membrane boundary, with no ligand bound. This indicates a state following substrate release but prior to ATP hydrolysis. Our results rationalize disease-causing mutations in human ABCB4 and suggest an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters.
History
DepositionJul 5, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 25, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.3May 22, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Assembly

Deposited unit
A: Phosphatidylcholine translocator ABCB4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)144,96512
Polymers140,8331
Non-polymers4,13211
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area6770 Å2
ΔGint-15 kcal/mol
Surface area44360 Å2
MethodPISA

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Components

#1: Protein Phosphatidylcholine translocator ABCB4 / ATP-binding cassette sub-family B member 4 / Multidrug resistance protein 3 / P-glycoprotein 3


Mass: 140833.406 Da / Num. of mol.: 1 / Mutation: E558Q, E1200Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB4, MDR3, PGY3 / Cell line (production host): Flp-In T-Rex 293 / Production host: Homo sapiens (human)
References: UniProt: P21439, P-type phospholipid transporter
#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C27H46O
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: Nucleotide Bound ABCB4 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.141 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: Flp-In T-Rex 293
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2150 mMSodium ChlorideNaCl1
35 mMMagnesium ChlorideMgCl2+1
45 mMATPC10H16N5O13P31
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: 5mM Magnesium Chloride 5mM ATP
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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 FIELD
Image recordingElectron dose: 68 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
Image scansMovie frames/image: 40

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Processing

EM software
IDNameVersionCategory
10RELION3initial Euler assignment
11RELION3final Euler assignment
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 193929 / Symmetry type: POINT

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