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- PDB-6c0v: Molecular structure of human P-glycoprotein in the ATP-bound, out... -

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Basic information

Entry
Database: PDB / ID: 6c0v
TitleMolecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation
ComponentsMultidrug resistance protein 1
KeywordsTRANSPORT PROTEIN / ABC transporter / ABCB1 / P-glycoprotein / cryo-EM / multidrug resistance / Structural Genomics / PSI-2 / Protein Structure Initiative
Function / homology
Function and homology information


carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / hormone transport / cellular response to nonylphenol / cellular response to borneol / response to codeine / response to cyclosporin A / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug ...carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / hormone transport / cellular response to nonylphenol / cellular response to borneol / response to codeine / response to cyclosporin A / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / terpenoid transport / ceramide floppase activity / negative regulation of sensory perception of pain / positive regulation of establishment of Sertoli cell barrier / regulation of intestinal absorption / cellular response to external biotic stimulus / response to quercetin / response to antineoplastic agent / ceramide translocation / floppase activity / Abacavir transmembrane transport / establishment of blood-retinal barrier / phosphatidylethanolamine flippase activity / protein localization to bicellular tight junction / phosphatidylcholine floppase activity / external side of apical plasma membrane / Atorvastatin ADME / xenobiotic transport across blood-brain barrier / response to thyroxine / establishment of blood-brain barrier / transepithelial transport / xenobiotic detoxification by transmembrane export across the plasma membrane / export across plasma membrane / P-type phospholipid transporter / cellular response to L-glutamate / response to vitamin A / ABC-type xenobiotic transporter / response to vitamin D / response to glycoside / response to alcohol / response to glucagon / intestinal absorption / ABC-type xenobiotic transporter activity / Prednisone ADME / cellular response to antibiotic / phospholipid translocation / cellular hyperosmotic salinity response / maintenance of blood-brain barrier / cellular response to alkaloid / efflux transmembrane transporter activity / transmembrane transporter activity / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / cellular response to dexamethasone stimulus / response to cadmium ion / transport across blood-brain barrier / lactation / xenobiotic metabolic process / regulation of chloride transport / response to progesterone / placenta development / stem cell proliferation / cellular response to estradiol stimulus / brush border membrane / female pregnancy / circadian rhythm / ABC-family proteins mediated transport / transmembrane transport / G2/M transition of mitotic cell cycle / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / response to hypoxia / apical plasma membrane / response to xenobiotic stimulus / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / extracellular exosome / 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'-TRIPHOSPHATE / ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsKim, Y.J. / Chen, J.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Science / Year: 2018
Title: Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation.
Authors: Youngjin Kim / Jue Chen /
Abstract: The multidrug transporter permeability (P)-glycoprotein is an adenosine triphosphate (ATP)-binding cassette exporter responsible for clinical resistance to chemotherapy. P-glycoprotein extrudes toxic ...The multidrug transporter permeability (P)-glycoprotein is an adenosine triphosphate (ATP)-binding cassette exporter responsible for clinical resistance to chemotherapy. P-glycoprotein extrudes toxic molecules and drugs from cells through ATP-powered conformational changes. Despite decades of effort, only the structures of the inward-facing conformation of P-glycoprotein are available. Here we present the structure of human P-glycoprotein in the outward-facing conformation, determined by cryo-electron microscopy at 3.4-angstrom resolution. The two nucleotide-binding domains form a closed dimer occluding two ATP molecules. The drug-binding cavity observed in the inward-facing structures is reorientated toward the extracellular space and compressed to preclude substrate binding. This observation indicates that ATP binding, not hydrolysis, promotes substrate release. The structure evokes a model in which the dynamic nature of P-glycoprotein enables translocation of a large variety of substrates.
History
DepositionJan 2, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 31, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2018Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Mar 7, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 3, 2018Group: Data collection / Refinement description / Category: refine
Revision 1.4Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Dec 18, 2019Group: Other / Category: atom_sites / cell
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][1] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.Z_PDB
Revision 1.6Mar 13, 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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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Multidrug resistance protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,7245
Polymers142,6611
Non-polymers1,0634
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 142660.922 Da / Num. of mol.: 1 / Mutation: E556Q, E1201Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB1, MDR1, PGY1 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: P08183, EC: 3.6.3.44
#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg

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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: Human P-glycoprotein E556Q, E1201Q / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.141 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameBuffer-ID
1200 mMNaCl1
220 mMTris1
310 mMMgCl21
410 mMATP1
53 mMFos-Choline-8, fluornate1
6150 uMVinblastine1
70.05 %DDM1
80.005 %Cholesteryl hemisuccinate1
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 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 FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 100 K / Temperature (min): 80 K
Image recordingAverage exposure time: 7 sec. / Electron dose: 80 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 2 / Num. of real images: 5747
EM imaging opticsEnergyfilter upper: 10 eV / Energyfilter lower: 10 eV
Image scansWidth: 3838 / Height: 3710 / Movie frames/image: 50 / Used frames/image: 1-50

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Processing

SoftwareName: REFMAC / Version: 5.8.0189 / Classification: refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
4CTFFINDCTF correction
7Coot0.8.7model fitting
9REFMACCCP4 7.0model refinement
10PHENIX1.11model refinement
11RELION1.4initial Euler assignment
12FREALIGNfinal Euler assignment
14FREALIGN3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 143451
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 143451 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: RECIPROCAL
RefinementResolution: 3.4→145.61 Å / Cor.coef. Fo:Fc: 0.979 / ESU R: 0.47
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.2419 --
obs0.2419 63353 99.97 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 266.758 Å2
Baniso -1Baniso -2Baniso -3
1--2.25 Å2-1 Å2-0.39 Å2
2--1.37 Å2-0.93 Å2
3---0.88 Å2
Refinement stepCycle: 1 / Total: 8976
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0070.0199138
ELECTRON MICROSCOPYr_bond_other_d00.028745
ELECTRON MICROSCOPYr_angle_refined_deg0.9621.96412365
ELECTRON MICROSCOPYr_angle_other_deg3.757320182
ELECTRON MICROSCOPYr_dihedral_angle_1_deg4.49851151
ELECTRON MICROSCOPYr_dihedral_angle_2_deg33.25223.83376
ELECTRON MICROSCOPYr_dihedral_angle_3_deg11.91151593
ELECTRON MICROSCOPYr_dihedral_angle_4_deg8.5791553
ELECTRON MICROSCOPYr_chiral_restr0.0520.21428
ELECTRON MICROSCOPYr_gen_planes_refined0.0030.0210092
ELECTRON MICROSCOPYr_gen_planes_other0.0020.021899
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it5.78127.3964613
ELECTRON MICROSCOPYr_mcbond_other5.7827.3944612
ELECTRON MICROSCOPYr_mcangle_it9.56141.1035761
ELECTRON MICROSCOPYr_mcangle_other9.56141.1065762
ELECTRON MICROSCOPYr_scbond_it5.39127.2694525
ELECTRON MICROSCOPYr_scbond_other5.3927.2684526
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other9.53840.8346605
ELECTRON MICROSCOPYr_long_range_B_refined15.31110924
ELECTRON MICROSCOPYr_long_range_B_other15.31110925
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.4→3.488 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rwork0.552 4686 -
Rfree-0 -
obs--99.85 %

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