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- PDB-6qex: Nanodisc reconstituted human ABCB1 in complex with UIC2 fab and taxol -

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Basic information

Entry
Database: PDB / ID: 6qex
TitleNanodisc reconstituted human ABCB1 in complex with UIC2 fab and taxol
Components
  • Multidrug resistance protein 1Multiple drug resistance
  • UIC2 Fab heavy chain
  • UIC2 Fab lightchain
KeywordsMEMBRANE PROTEIN / ABCB1 / p-glycoprotein / p-gp / multidrug exporter / ABC transporter
Function / homology
Function and homology information


external side of apical plasma membrane / ceramide translocation / transporter activity / positive regulation of anion channel activity / floppase activity / ceramide floppase activity / phosphatidylcholine floppase activity / phosphatidylethanolamine flippase activity / xenobiotic transport across blood-brain barrier / regulation of response to osmotic stress ...external side of apical plasma membrane / ceramide translocation / transporter activity / positive regulation of anion channel activity / floppase activity / ceramide floppase activity / phosphatidylcholine floppase activity / phosphatidylethanolamine flippase activity / xenobiotic transport across blood-brain barrier / regulation of response to osmotic stress / export across plasma membrane / ABC-type xenobiotic transporter / P-type phospholipid transporter / transepithelial transport / stem cell proliferation / ATPase-coupled xenobiotic transmembrane transporter activity / phospholipid translocation / xenobiotic transmembrane transporter activity / efflux transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / regulation of chloride transport / transmembrane transport / G2/M transition of mitotic cell cycle / apical plasma membrane / response to drug / ATPase activity / ubiquitin protein ligase binding / cell surface / extracellular exosome / membrane / integral component of membrane / ATP binding / plasma membrane
AAA+ ATPase domain / Multidrug resistance protein 1 / ABC transporter-like / ABC transporter type 1, transmembrane domain / ABC transporter, conserved site / P-loop containing nucleoside triphosphate hydrolase / ABC transporter type 1, transmembrane domain superfamily / Type I protein exporter / ABC transporter / ABC transporter transmembrane region ...AAA+ ATPase domain / Multidrug resistance protein 1 / ABC transporter-like / ABC transporter type 1, transmembrane domain / ABC transporter, conserved site / P-loop containing nucleoside triphosphate hydrolase / ABC transporter type 1, transmembrane domain superfamily / Type I protein exporter / ABC transporter / ABC transporter transmembrane region / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
ATP-dependent translocase ABCB1
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsAlam, A. / Locher, K.P.
Funding support Switzerland, 2items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
European Molecular Biology Organization Switzerland
CitationJournal: Science / Year: 2019
Title: Structural insight into substrate and inhibitor discrimination by human P-glycoprotein.
Authors: Amer Alam / Julia Kowal / Eugenia Broude / Igor Roninson / Kaspar P Locher /
Abstract: ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic ...ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic drug delivery. We determined the 3.5-angstrom cryo-electron microscopy structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the adenosine triphosphate-hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport.
Validation Report
SummaryFull reportAbout validation report
History
DepositionJan 8, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Other / Category: atom_sites / cell
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.Z_PDB

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Structure visualization

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Assembly

Deposited unit
A: Multidrug resistance protein 1
B: UIC2 Fab lightchain
C: UIC2 Fab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)199,53125
Polymers190,3313
Non-polymers9,20022
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area18490 Å2
ΔGint-41 kcal/mol
Surface area73480 Å2
MethodPISA

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Components

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Protein/peptide , 3 types, 3 molecules ABC

#1: Protein/peptide Multidrug resistance protein 1 / Multiple drug resistance / ATP-binding cassette sub-family B member 1 / P-glycoprotein 1


Mass: 141628.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB1, MDR1, PGY1 / Production host: Homo sapiens (human)
References: UniProt: P08183, ABC-type xenobiotic transporter
#2: Protein/peptide UIC2 Fab lightchain


Mass: 24321.039 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#3: Protein/peptide UIC2 Fab heavy chain


Mass: 24381.281 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)

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Non-polymers , 4 types, 22 molecules

#4: Chemical ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
#5: Chemical
ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C27H46O
#6: Chemical ChemComp-TA1 / TAXOL / Paclitaxel


Mass: 853.906 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C47H51NO14 / Comment: drug*YM
#7: Chemical ChemComp-3PE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / 3-SN-PHOSPHATIDYLETHANOLAMINE / Phosphatidylethanolamine


Mass: 748.065 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C41H82NO8P / Comment: phospholipid*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

Component

Type: COMPLEX

IDNameEntity IDParent-IDSource
1Nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol1, 2, 30MULTIPLE SOURCES
2nanodisc reconstituted human ABCB111RECOMBINANT
3UIC2 Fab2, 31NATURAL
Molecular weightValue: 0.2 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Mus musculus (house mouse)10090
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / Humidity: 100 % / Chamber temperature: 277 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 FIELDBright-field microscopy
Image recordingElectron dose: 2.1 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.14_3260: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 262191 / Symmetry type: POINT
RefinementStereochemistry target values: CDL v1.2
Refine LS restraints

Refinement-ID: ELECTRON MICROSCOPY

TypeDev idealNumber
f_bond_d0.008713569
f_angle_d1.140718473
f_chiral_restr0.06462149
f_plane_restr0.00682232
f_dihedral_angle_d16.94677881

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