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- PDB-6qee: Nanodisc reconstituted Human-mouse chimeric ABCB1 (ABCB1HM)-EQ mu... -

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Basic information

Entry
Database: PDB / ID: 6qee
TitleNanodisc reconstituted Human-mouse chimeric ABCB1 (ABCB1HM)-EQ mutant in complex with UIC2 Fab and Zosuquidar.
Components
  • (UIC2 Antigen Binding Fragment ...) x 2
  • ABCB1HM-EQ
KeywordsMEMBRANE PROTEIN / ABCB1 / p-glycoprotein / p-gp / multidrug transporter / ABC transporter / zosuquidar / membrane transporter
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta / 1,2-Distearoyl-sn-glycerophosphoethanolamine / CHOLESTEROL / Zosuquidar
Function and homology information
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsAlam, A.
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.
History
DepositionJan 7, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Other / Category: atom_sites
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3]
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Jun 2, 2021Group: Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms

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Structure visualization

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Assembly

Deposited unit
A: ABCB1HM-EQ
B: UIC2 Antigen Binding Fragment Light chain
C: UIC2 Antigen Binding Fragment Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)197,50416
Polymers192,3303
Non-polymers5,17313
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11680 Å2
ΔGint-35 kcal/mol
Surface area74240 Å2
MethodPISA

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Components

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Antibody , 2 types, 2 molecules BC

#2: Antibody UIC2 Antigen Binding Fragment Light chain


Mass: 24321.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
#3: Antibody UIC2 Antigen Binding Fragment Heavy Chain


Mass: 24381.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)

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Protein / Sugars , 2 types, 4 molecules A

#1: Protein ABCB1HM-EQ


Mass: 143627.828 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 3 types, 10 molecules

#5: Chemical ChemComp-ZQU / Zosuquidar / Zosuquidar


Mass: 527.604 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H31F2N3O2 / Comment: antineoplastic*YM
#6: Chemical
ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C27H46O
#7: Chemical ChemComp-3PE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / 3-SN-PHOSPHATIDYLETHANOLAMINE / Phosphatidylethanolamine


Mass: 748.065 Da / Num. of mol.: 1 / 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
IDNameTypeEntity IDParent-IDSource
1Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidarCOMPLEX#1-#30MULTIPLE SOURCES
2ABCB1HMCOMPLEX#11RECOMBINANT
3UIC2 FabCOMPLEX#2-#31RECOMBINANT
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)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Mus musculus (house mouse)10090
Buffer solutionpH: 7.5
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil R1.2/1.3
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
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 291197 / Symmetry type: POINT
RefinementStereochemistry target values: CDL v1.2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.010313274
ELECTRON MICROSCOPYf_angle_d1.187918029
ELECTRON MICROSCOPYf_chiral_restr0.06412069
ELECTRON MICROSCOPYf_plane_restr0.00772227
ELECTRON MICROSCOPYf_dihedral_angle_d13.56557775

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