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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 / homologyType I protein exporter / ABC transporter-like / ABC-family proteins mediated transport / Abacavir transmembrane transport / ABC transporter integral membrane type-1 fused domain profile. / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporters family signature. / ABC transporter transmembrane region / ABC transporter / ABC transporter type 1, transmembrane domain superfamily ...Type I protein exporter / ABC transporter-like / ABC-family proteins mediated transport / Abacavir transmembrane transport / ABC transporter integral membrane type-1 fused domain profile. / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporters family signature. / ABC transporter transmembrane region / ABC transporter / ABC transporter type 1, transmembrane domain superfamily / Multidrug resistance protein 1 / P-loop containing nucleoside triphosphate hydrolase / ABC transporter, conserved site / ABC transporter type 1, transmembrane domain / AAA+ ATPase domain / ceramide translocation / ceramide-translocating ATPase activity / positive regulation of anion channel activity / phosphatidylethanolamine-translocating ATPase activity / ABC-type xenobiotic transporter / phosphatidylcholine-translocating ATPase activity / regulation of response to osmotic stress / phospholipid translocation / xenobiotic transmembrane transporting ATPase activity / stem cell proliferation / ATPase activity, coupled to transmembrane movement of substances / transporter activity / regulation of chloride transport / transmembrane transport / apical plasma membrane / G2/M transition of mitotic cell cycle / response to drug / cell surface / extracellular exosome / membrane / integral component of membrane / ATP binding / plasma membrane / Multidrug resistance protein 1
Function and homology information
Specimen sourceHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 3.6 Å resolution
AuthorsAlam, A. / Locher, K.P.
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
DateDeposition: Jan 8, 2019 / Release: Feb 27, 2019

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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
Polyers190,3313
Non-polymers9,20022
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)18490
ΔGint (kcal/M)-41
Surface area (Å2)73480
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: (gene. exp.) Homo sapiens (human) / Gene: ABCB1, MDR1, PGY1P-glycoprotein / 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: (natural) Mus musculus (house mouse)
#3: Protein/peptide UIC2 Fab heavy chain


Mass: 24381.281 Da / Num. of mol.: 1 / Source: (natural) Mus musculus (house mouse)

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Non-polymers , 4 types, 22 molecules

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


Mass: 221.208 Da / Num. of mol.: 3 / Formula: C8H15NO6 / N-Acetylglucosamine
#5: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 16 / Formula: C27H46O / Cholesterol
#6: Chemical ChemComp-TA1 / TAXOL


Mass: 853.906 Da / Num. of mol.: 1 / Formula: C47H51NO14 / Paclitaxel
#7: Chemical ChemComp-3PE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / 3-SN-PHOSPHATIDYLETHANOLAMINE


Mass: 748.065 Da / Num. of mol.: 2 / Formula: C41H82NO8P / Comment: phospholipid *YM

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / Reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent IDSource
1Nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxolCOMPLEX1, 2, 30MULTIPLE SOURCES
2nanodisc reconstituted human ABCB1COMPLEX11RECOMBINANT
3UIC2 FabCOMPLEX2, 31NATURAL
Molecular weightValue: 0.2 MDa / Experimental value: YES
Source (natural)
IDEntity assembly IDNcbi tax IDOrganism
129606Homo sapiens (human)
2310090Mus musculus (house mouse)
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 kelvins

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyMicroscope model: 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 / Number of particles: 262191 / Symmetry type: POINT
RefineStereochemistry target values: CDL v1.2
Refine LS restraints
Refine IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.008713569
ELECTRON MICROSCOPYf_angle_d1.140718473
ELECTRON MICROSCOPYf_chiral_restr0.06462149
ELECTRON MICROSCOPYf_plane_restr0.00682232
ELECTRON MICROSCOPYf_dihedral_angle_d16.94677881

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