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- PDB-5uj9: Cryo-EM structure of bovine multidrug resistance protein 1 (MRP1) -

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Basic information

Entry
Database: PDB / ID: 5uj9
TitleCryo-EM structure of bovine multidrug resistance protein 1 (MRP1)
Componentsbovine multidrug resistance protein 1 (MRP1),Multidrug resistance-associated protein 1
KeywordsTRANSPORT PROTEIN / ABC transporter / multidrug resistance
Function / homology
Function and homology information


Heme degradation / Synthesis of Leukotrienes (LT) and Eoxins (EX) / cyclic nucleotide transport / Transport of RCbl within the body / Paracetamol ADME / leukotriene transport / glutathione transmembrane transporter activity / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / glutathione transmembrane transport ...Heme degradation / Synthesis of Leukotrienes (LT) and Eoxins (EX) / cyclic nucleotide transport / Transport of RCbl within the body / Paracetamol ADME / leukotriene transport / glutathione transmembrane transporter activity / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / glutathione transmembrane transport / ABC-family proteins mediated transport / Cytoprotection by HMOX1 / ABC-type xenobiotic transporter / ABC-type xenobiotic transporter activity / xenobiotic transport / lipid transport / xenobiotic transmembrane transporter activity / ABC-type transporter activity / positive regulation of inflammatory response / basolateral plasma membrane / response to xenobiotic stimulus / ATP hydrolysis activity / ATP binding
Similarity search - Function
Multi drug resistance-associated protein / 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. ...Multi drug resistance-associated protein / 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
Multidrug resistance-associated protein 1
Similarity search - Component
Biological speciesBos taurus (cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.49 Å
AuthorsJohnson, Z.L. / Chen, J.
Funding support United States, 3items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
The Rockefeller University United States
Jane Coffin Childs Memorial Fund for Medical Research United States
CitationJournal: Cell / Year: 2017
Title: Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1.
Authors: Zachary Lee Johnson / Jue Chen /
Abstract: The multidrug resistance protein MRP1 is an ATP-binding cassette (ABC) transporter that confers resistance to many anticancer drugs and plays a role in the disposition and efficacy of several ...The multidrug resistance protein MRP1 is an ATP-binding cassette (ABC) transporter that confers resistance to many anticancer drugs and plays a role in the disposition and efficacy of several opiates, antidepressants, statins, and antibiotics. In addition, MRP1 regulates redox homeostasis, inflammation, and hormone secretion. Using electron cryomicroscopy, we determined the molecular structures of bovine MRP1 in two conformations: an apo form at 3.5 Å without any added substrate and a complex form at 3.3 Å with one of its physiological substrates, leukotriene C. These structures show that by forming a single bipartite binding site, MRP1 can recognize a spectrum of substrates with different chemical structures. We also observed large conformational changes induced by leukotriene C, explaining how substrate binding primes the transporter for ATP hydrolysis. Structural comparison of MRP1 and P-glycoprotein advances our understanding of the common and unique properties of these two important molecules in multidrug resistance to chemotherapy.
History
DepositionJan 17, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 15, 2017Group: Database references
Revision 1.2Mar 22, 2017Group: Database references
Revision 1.3Mar 29, 2017Group: Source and taxonomy
Revision 1.4Nov 8, 2017Group: Data processing / Derived calculations / Category: em_software / pdbx_struct_assembly
Item: _em_software.name / _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details
Revision 1.5Oct 3, 2018Group: Data collection / Other ...Data collection / Other / Refinement description / Structure summary
Category: cell / em_entity_assembly / refine
Item: _cell.length_a / _cell.length_b ..._cell.length_a / _cell.length_b / _cell.length_c / _em_entity_assembly.entity_id_list
Revision 1.6Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.7Dec 18, 2019Group: Other / Category: atom_sites
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]
Revision 1.8Mar 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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Assembly

Deposited unit
A: bovine multidrug resistance protein 1 (MRP1),Multidrug resistance-associated protein 1


Theoretical massNumber of molelcules
Total (without water)159,7021
Polymers159,7021
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein bovine multidrug resistance protein 1 (MRP1),Multidrug resistance-associated protein 1 / ATP-binding cassette sub-family C member 1 / Leukotriene C(4) transporter / LTC4 transporter


Mass: 159701.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: ABCC1, MRP1 / Cell line (production host): HEK293S GntI- / Production host: Homo sapiens (human) / References: UniProt: Q8HXQ5
Sequence detailsResidues 31-194, corresponding to TMD0, are modeled as poly-alanine. The register in this region ...Residues 31-194, corresponding to TMD0, are modeled as poly-alanine. The register in this region could not be confidently established and thus the numbering assigned to the residues is putative. The poly-alanine regions have been renamed as unknown

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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: bovine multidrug resistance protein 1 (MRP1) / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.17 MDa / Experimental value: NO
Source (natural)Organism: Bos taurus (cattle)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293S GntI- / Plasmid: Baculovirus
Buffer solutionpH: 8
Buffer component
IDConc.NameBuffer-ID
1150 mMKCl1
250 mMTris1
32 mMMgCl21
42 mMDTT1
50.06 %Digitonin1
63 mMFos-Choline-8, fluorinated1
SpecimenConc.: 4.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD
Grid type: Quantifoil R1.2/1.3 400-mesh Au Holey Carbon Grids
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 FIELDBright-field microscopy / Nominal magnification: 37000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 700 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: 84 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2232
Image scansWidth: 3710 / Height: 3838 / Movie frames/image: 50 / Used frames/image: 1-50

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Processing

SoftwareName: REFMAC / Version: 5.8.0158 / Classification: refinement
EM software
IDNameVersionCategory
1RELION1.4particle selection
2SerialEMimage acquisition
4CTFFIND4CTF correction
7Coot0.8.7model fitting
9RELION1.4initial Euler assignment
10FREALIGNfinal Euler assignment
12FREALIGN3D reconstruction
13PHENIX1.11model refinement
14REFMACCCP4 7.0model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 251986
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.49 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 251986 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: RECIPROCAL
RefinementResolution: 3.49→148 Å / Cor.coef. Fo:Fc: 0.969 / ESU R: 0.448
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.28564 --
obs0.28564 88282 99.99 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 265.842 Å2
Baniso -1Baniso -2Baniso -3
1--6.2 Å2-0.4 Å22.19 Å2
2--4.38 Å20.61 Å2
3---1.82 Å2
Refinement stepCycle: 1 / Total: 9857
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0080.01910042
ELECTRON MICROSCOPYr_bond_other_d00.029686
ELECTRON MICROSCOPYr_angle_refined_deg1.0281.95713640
ELECTRON MICROSCOPYr_angle_other_deg3.791322312
ELECTRON MICROSCOPYr_dihedral_angle_1_deg5.54851286
ELECTRON MICROSCOPYr_dihedral_angle_2_deg31.40223.795390
ELECTRON MICROSCOPYr_dihedral_angle_3_deg12.13151667
ELECTRON MICROSCOPYr_dihedral_angle_4_deg12.6411555
ELECTRON MICROSCOPYr_chiral_restr0.0540.21619
ELECTRON MICROSCOPYr_gen_planes_refined0.0030.0211130
ELECTRON MICROSCOPYr_gen_planes_other0.0020.022045
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_it6.37427.3975171
ELECTRON MICROSCOPYr_mcbond_other6.37327.3955170
ELECTRON MICROSCOPYr_mcangle_it10.48941.0736448
ELECTRON MICROSCOPYr_mcangle_other10.48841.0756449
ELECTRON MICROSCOPYr_scbond_it6.42426.8854871
ELECTRON MICROSCOPYr_scbond_other6.42326.8794869
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other11.37440.2817192
ELECTRON MICROSCOPYr_long_range_B_refined17.8412003
ELECTRON MICROSCOPYr_long_range_B_other17.8412004
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.49→3.581 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rwork0.765 6547 -
Rfree-0 -
obs--99.91 %

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