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- PDB-7otg: Structure of ABCB1/P-glycoprotein in the presence of the CFTR pot... -

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Basic information

Entry
Database: PDB / ID: 7otg
TitleStructure of ABCB1/P-glycoprotein in the presence of the CFTR potentiator ivacaftor
ComponentsMultidrug resistance protein 1A
KeywordsMEMBRANE PROTEIN / ABCB1 / ABC Transporters / Membrane Proteins / Ivacaftor / MDR1 / Multidrug resistance / cryo-em
Function / homology
Function and homology information


hormone transport / cellular response to nonylphenol / cellular response to borneol / response to codeine / response to cyclosporin A / Atorvastatin ADME / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / negative regulation of sensory perception of pain ...hormone transport / cellular response to nonylphenol / cellular response to borneol / response to codeine / response to cyclosporin A / Atorvastatin ADME / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / negative regulation of sensory perception of pain / positive regulation of establishment of Sertoli cell barrier / regulation of intestinal absorption / response to quercetin / cellular response to external biotic stimulus / response to antineoplastic agent / Prednisone ADME / terpenoid transport / ceramide floppase activity / establishment of blood-retinal barrier / response to glycoside / protein localization to bicellular tight junction / ceramide translocation / floppase activity / ABC-family proteins mediated transport / response to thyroxine / establishment of blood-brain barrier / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity / cellular response to L-glutamate / xenobiotic transport across blood-brain barrier / intercellular canaliculus / xenobiotic detoxification by transmembrane export across the plasma membrane / response to vitamin D / export across plasma membrane / P-type phospholipid transporter / ABC-type xenobiotic transporter / response to alcohol / response to vitamin A / response to glucagon / intestinal absorption / ABC-type xenobiotic transporter activity / cellular response to antibiotic / phospholipid translocation / cellular hyperosmotic salinity response / cellular response to alkaloid / maintenance of blood-brain barrier / efflux transmembrane transporter activity / transmembrane transporter activity / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / response to cadmium ion / lactation / cellular response to dexamethasone stimulus / response to progesterone / female pregnancy / placenta development / cellular response to estradiol stimulus / brush border membrane / circadian rhythm / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / response to hypoxia / apical plasma membrane / response to xenobiotic stimulus / ATP hydrolysis activity / ATP binding / 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
Chem-VX7 / ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.4 Å
AuthorsFord, R.C. / Barbieri, A. / Thonghin, N. / Shafi, T. / Prince, S.M. / Collins, R.F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Membranes (Basel) / Year: 2021
Title: Structure of ABCB1/P-Glycoprotein in the Presence of the CFTR Potentiator Ivacaftor.
Authors: Alessandro Barbieri / Nopnithi Thonghin / Talha Shafi / Stephen M Prince / Richard F Collins / Robert C Ford /
Abstract: ABCB1/P-glycoprotein is an ATP binding cassette transporter that is involved in the clearance of xenobiotics, and it affects the disposition of many drugs in the body. Conformational flexibility of ...ABCB1/P-glycoprotein is an ATP binding cassette transporter that is involved in the clearance of xenobiotics, and it affects the disposition of many drugs in the body. Conformational flexibility of the protein within the membrane is an intrinsic part of its mechanism of action, but this has made structural studies challenging. Here, we have studied different conformations of P-glycoprotein simultaneously in the presence of ivacaftor, a known competitive inhibitor. In order to conduct this, we used high contrast cryo-electron microscopy imaging with a Volta phase plate. We associate the presence of ivacaftor with the appearance of an additional density in one of the conformational states detected. The additional density is in the central aqueous cavity and is associated with a wider separation of the two halves of the transporter in the inward-facing state. Conformational changes to the nucleotide-binding domains are also observed and may help to explain the stimulation of ATPase activity that occurs when transported substrate is bound in many ATP binding cassette transporters.
History
DepositionJun 10, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 8, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 5, 2022Group: Database references / Category: citation
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 17, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / em_admin
Item: _citation.country / _em_admin.last_update

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Assembly

Deposited unit
A: Multidrug resistance protein 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,2702
Polymers141,8781
Non-polymers3921
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area55400 Å2

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Components

#1: Protein Multidrug resistance protein 1A / ATP-binding cassette sub-family B member 1A / MDR1A / Multidrug resistance protein 3 / P-glycoprotein 3


Mass: 141877.875 Da / Num. of mol.: 1 / Mutation: 0
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Abcb1a, Abcb4, Mdr1a, Mdr3, Pgy-3, Pgy3 / Production host: Komagataella pastoris (fungus) / References: UniProt: P21447, EC: 3.6.3.44
#2: Chemical ChemComp-VX7 / N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide


Mass: 392.491 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H28N2O3 / Comment: medication*YM
Has ligand of interestN

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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: Structure of ABCB1/P-glycoprotein in the presence of the CFTR potentiator ivacaftor
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Komagataella pastoris (fungus)
Buffer solutionpH: 8
SpecimenConc.: 1.1 mg/ml / Embedding 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: 64 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM imaging opticsPhase plate: VOLTA PHASE PLATE / Spherical aberration corrector: 2.7

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Processing

EM software
IDNameCategory
4CTFFINDCTF correction
10cisTEMinitial Euler assignment
11cisTEMfinal Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 317000
3D reconstructionResolution: 5.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 104000 / Num. of class averages: 1 / Symmetry type: POINT

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