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- PDB-6q81: Structure of P-glycoprotein(ABCB1) in the post-hydrolytic state -

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Entry
Database: PDB / ID: 6q81
TitleStructure of P-glycoprotein(ABCB1) in the post-hydrolytic state
ComponentsP-glycoprotein (ABCB1)
KeywordsMEMBRANE PROTEIN / P-glycoprotein / ABCB1 / ATP-binding cassette / transporter / protein structure
Function / homology
Function and homology information


Atorvastatin ADME / aldosterone secretion / Prednisone ADME / neural tissue regeneration / cellular response to nonylphenol / cellular response to borneol / response to codeine / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug ...Atorvastatin ADME / aldosterone secretion / Prednisone ADME / neural tissue regeneration / cellular response to nonylphenol / cellular response to borneol / response to codeine / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / terpenoid transport / ceramide floppase activity / regulation of intestinal absorption / cellular response to external biotic stimulus / response to cyclosporin A / response to antineoplastic agent / positive regulation of establishment of Sertoli cell barrier / negative regulation of sensory perception of pain / carboxylic acid transmembrane transport / floppase activity / ceramide translocation / response to quercetin / ABC-family protein mediated transport / carboxylic acid transmembrane transporter activity / establishment of blood-retinal barrier / phosphatidylethanolamine flippase activity / protein localization to bicellular tight junction / phosphatidylcholine floppase activity / response to thyroxine / xenobiotic transport across blood-brain barrier / establishment of blood-brain barrier / intercellular canaliculus / export across plasma membrane / P-type phospholipid transporter / cardiac muscle cell differentiation / xenobiotic detoxification by transmembrane export across the plasma membrane / transepithelial transport / ABC-type xenobiotic transporter / cellular response to L-glutamate / response to vitamin A / adult heart development / response to glucagon / response to vitamin D / intestinal absorption / response to alcohol / response to glycoside / ABC-type xenobiotic transporter activity / phospholipid translocation / cellular hyperosmotic salinity response / cellular response to alkaloid / female gonad development / cellular response to antibiotic / maintenance of blood-brain barrier / exploration behavior / ATPase-coupled transmembrane transporter activity / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / cellular response to dexamethasone stimulus / response to cadmium ion / transmembrane transporter activity / xenobiotic transport / lactation / response to progesterone / proteasomal protein catabolic process / neurogenesis / regulation of chloride transport / placenta development / stem cell proliferation / cellular response to estradiol stimulus / brush border membrane / female pregnancy / circadian rhythm / G2/M transition of mitotic cell cycle / cellular response to tumor necrosis factor / response to toxic substance / epidermal growth factor receptor signaling pathway / heart development / cellular response to lipopolysaccharide / gene expression / response to hypoxia / apical plasma membrane / response to xenobiotic stimulus / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / ATP binding / membrane / plasma membrane / 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'-DIPHOSPHATE / ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 7.9 Å
AuthorsFord, R.C. / Thonghin, N. / Collins, R.F. / Barbieri, A. / Shafi, T. / Siebert, A.
CitationJournal: BMC Struct Biol / Year: 2018
Title: Novel features in the structure of P-glycoprotein (ABCB1) in the post-hydrolytic state as determined at 7.9 Å resolution.
Authors: Nopnithi Thonghin / Richard F Collins / Alessandro Barbieri / Talha Shafi / Alistair Siebert / Robert C Ford /
Abstract: BACKGROUND: P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. ...BACKGROUND: P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. Although several P-glycoprotein structures are available, these are either at low resolution, or represent mutated and/or quiescent states of the protein.
RESULTS: In the post-hydrolytic state the structure of the wild-type protein has been resolved at about 8 Å resolution. The cytosolic nucleotide-binding domains (NBDs) are separated but ADP ...RESULTS: In the post-hydrolytic state the structure of the wild-type protein has been resolved at about 8 Å resolution. The cytosolic nucleotide-binding domains (NBDs) are separated but ADP remains bound, especially at the first NBD. Gaps in the transmembrane domains (TMDs) that connect to an inner hydrophilic cavity are filled by density emerging from the annular detergent micelle. The NBD-TMD linker is partly resolved, being located between the NBDs and close to the Signature regions involved in cooperative NBD dimerization. This, and the gap-filling detergent suggest steric impediment to NBD dimerization in the post-hydrolytic state. Two central regions of density lie in two predicted drug-binding sites, implying that the protein may adventitiously bind hydrophobic substances even in the post-hydrolytic state. The previously unresolved N-terminal extension was observed, and the data suggests these 30 residues interact with the headgroup region of the lipid bilayer.
CONCLUSION: The structural data imply that (i) a low basal ATPase activity is ensured by steric blockers of NBD dimerization and (ii) allocrite access to the central cavity may be structurally linked ...CONCLUSION: The structural data imply that (i) a low basal ATPase activity is ensured by steric blockers of NBD dimerization and (ii) allocrite access to the central cavity may be structurally linked to NBD dimerization, giving insights into the mechanism of drug-stimulation of P-glycoprotein activity.
History
DepositionDec 13, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 26, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update
Revision 1.2May 15, 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: P-glycoprotein (ABCB1)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,6613
Polymers140,8071
Non-polymers8542
Water00
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area1100 Å2
ΔGint-12 kcal/mol
Surface area55040 Å2
MethodPISA

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Components

#1: Protein P-glycoprotein (ABCB1)


Mass: 140806.766 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P21447
#2: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM

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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: P-glycoprotein trapped in the post-hydrolytic state. / Type: ORGANELLE OR CELLULAR COMPONENT / Details: ATP and Vanadate added / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 142 kDa/nm / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Saccharomyces cerevisiae (brewer's yeast)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 70 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameCategory
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionMethod: SINGLE PARTICLE / Resolution: 7.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 135357 / Symmetry type: POINT

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