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- EMDB-7099: Cryo-EM structure of ATP-bound, outward-facing bovine multidrug r... -

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Basic information

Entry
Database: EMDB / ID: EMD-7099
TitleCryo-EM structure of ATP-bound, outward-facing bovine multidrug resistance protein 1 (MRP1)
Map dataFull map scaled to model, B-factor sharpened with a sharpening factor of -75 A^2.
Sample
  • Complex: bovine multidrug resistance protein 1 (MRP1) E1454Q
    • Protein or peptide: Multidrug resistance-associated protein 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: CHOLESTEROL
KeywordsABC transporter / multidrug resistance / outward facing / TRANSPORT PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.14 Å
AuthorsJohnson ZL / Chen J
Funding support United States, 3 items
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: 2018
Title: ATP Binding Enables Substrate Release from Multidrug Resistance Protein 1.
Authors: Zachary Lee Johnson / Jue Chen /
Abstract: The multidrug resistance protein MRP1 is an ATP-driven pump that confers resistance to chemotherapy. Previously, we have shown that intracellular substrates are recruited to a bipartite binding site ...The multidrug resistance protein MRP1 is an ATP-driven pump that confers resistance to chemotherapy. Previously, we have shown that intracellular substrates are recruited to a bipartite binding site when the transporter rests in an inward-facing conformation. A key question remains: how are high-affinity substrates transferred across the membrane and released outside the cell? Using electron cryomicroscopy, we show here that ATP binding opens the transport pathway to the extracellular space and reconfigures the substrate-binding site such that it relinquishes its affinity for substrate. Thus, substrate is released prior to ATP hydrolysis. With this result, we now have a complete description of the conformational cycle that enables substrate transfer in a eukaryotic ABC exporter.
History
DepositionOct 31, 2017-
Header (metadata) releaseNov 22, 2017-
Map releaseDec 27, 2017-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.5
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 1.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6bhu
  • Surface level: 1.5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_7099.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map scaled to model, B-factor sharpened with a sharpening factor of -75 A^2.
Voxel sizeX=Y=Z: 0.817 Å
Density
Contour LevelBy AUTHOR: 1.5 / Movie #1: 1.5
Minimum - Maximum-4.9317555 - 9.895077000000001
Average (Standard dev.)0.008479072 (±0.23633268)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 313.728 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8170.8170.817
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z313.728313.728313.728
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-4.9329.8950.008

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Supplemental data

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Additional map: Full map scaled to model, unsharpened.

Fileemd_7099_additional.map
AnnotationFull map scaled to model, unsharpened.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Half map 2 scaled to model, unsharpened.

Fileemd_7099_half_map_1.map
AnnotationHalf map 2 scaled to model, unsharpened.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Half map 1 scaled to model, unsharpened.

Fileemd_7099_half_map_2.map
AnnotationHalf map 1 scaled to model, unsharpened.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : bovine multidrug resistance protein 1 (MRP1) E1454Q

EntireName: bovine multidrug resistance protein 1 (MRP1) E1454Q
Components
  • Complex: bovine multidrug resistance protein 1 (MRP1) E1454Q
    • Protein or peptide: Multidrug resistance-associated protein 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: CHOLESTEROL

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Supramolecule #1: bovine multidrug resistance protein 1 (MRP1) E1454Q

SupramoleculeName: bovine multidrug resistance protein 1 (MRP1) E1454Q / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Bos taurus (cattle)
Molecular weightTheoretical: 170 KDa

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Macromolecule #1: Multidrug resistance-associated protein 1

MacromoleculeName: Multidrug resistance-associated protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (cattle)
Molecular weightTheoretical: 183.074062 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) ...String:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)MAL RDFCSVDGSD LFWEWNVTWN TSNPDFTKCF QNTVLVW VP CSYLWVCFPF YFLYLSHHDR GYIQMTHLNK AKTALGFLLW IVCWADLFYS FWERSMGKLL APVFLVSPTL LGITMLLA T FLIQIERRRG VQSSGIMLTF WLIALLCALA ILRSKIMTAL KEDARVDVFR DVTFYIYFSL VLIQLVLSCF SDRSPLFSE TINDPNPCPE SSASFLSRIT FWWITGMMVQ GYRQPLESTD LWSLNKEDTS EQVVPVLVKN WKKECAKSRK QPVKIVYSSK DPAKPKGSS KVDVNEEAEA LIVKCPQKER DPSLFKVLYK TFGPYFLMSF LFKAVHDLMM FAGPEILKLL INFVNDKKAP E WQGYFYTA LLFISACLQT LVLHQYFHIC FVSGMRIKTA VIGAVYRKAL VITNAARKSS TVGEIVNLMS VDAQRFMDLA TY INMIWSA PLQVILALYL LWLNLGPSVL AGVAVMVLMV PLNAVMAMKT KTYQVAHMKS KDNRIKLMNE ILNGIKVLKL YAW ELAFKD KVLAIRQEEL KVLKKSAYLA AVGTFTWVCT PFLVALSTFA VYVTVDENNI LDAQKAFVSL ALFNILRFPL NILP MVISS IVQASVSLKR LRVFLSHEDL DPDSIQRRPI KDAGATNSIT VKNATFTWAR NDPPTLHGIT FSVPEGSLVA VVGQV GCGK SSLLSALLAE MDKVEGHVTV KGSVAYVPQQ AWIQNISLRE NILFGRQLQE RYYKAVVEAC ALLPDLEILP SGDRTE IGE KGVNLSGGQK QRVSLARAVY CDSDVYLLDD PLSAVDAHVG KHIFENVIGP KGLLKNKTRL LVTHAISYLP QMDVIIV MS GGKISEMGSY QELLARDGAF AEFLRTYASA EQEQGQPEDG LAGVGGPGKE VKQMENGMLV TDTAGKQMQR QLSSSSSY S RDVSQHHTST AELRKPGPTE ETWKLVEADK AQTGQVKLSV YWDYMKAIGL FISFLSIFLF LCNHVASLVS NYWLSLWTD DPIVNGTQEH TQVRLSVYGA LGISQGITVF GYSMAVSIGG IFASRRLHLD LLHNVLRSPI SFFERTPSGN LVNRFSKELD TVDSMIPQV IKMFMGSLFN VIGACIIILL ATPMAAVIIP PLGLIYFFVQ RFYVASSRQL KRLESVSRSP VYSHFNETLL G VSVIRAFE EQERFIRQSD LKVDENQKAY YPSIVANRWL AVRLECVGNC IVLFASLFAV ISRHSLSAGL VGLSVSYSLQ VT TYLNWLV RMSSEMETNI VAVERLKEYS ETEKEAPWQI QDMAPPKDWP QVGRVEFRDY GLRYREDLDL VLKHINVTID GGE KVGIVG RTGAGKSSLT LGLFRIKESA EGEIIIDDIN IAKIGLHDLR FKITIIPQDP VLFSGSLRMN LDPFSQYSDE EVWT SLELA HLKGFVSALP DKLNHECAEG GENLSVGQRQ LVCLARALLR KTKILVLDQA TAAVDLETDD LIQSTIRTQF DDCTV LTIA HRLNTIMDYT RVIVLDKGEI QEWGSPSDLL QQRGLFYSMA KDSGLVSNSL EVLFQ

UniProtKB: Multidrug resistance-associated protein 1

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 3 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4.9 mg/mL
BufferpH: 8
Component:
ConcentrationName
150.0 mMKCl
50.0 mMTris
2.0 mMMgCl2
2.0 mMDTT
0.06 %Digitonin
3.0 mMFos-Choline-8, fluorinated
80.0 uMLeukotriene C4
2.5 %DMSODimethyl sulfoxide
GridModel: Quantifoil R1.2/1.3 400-mesh Au Holey Carbon Grids / Material: GOLD / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 12 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 37000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
TemperatureMin: 80.0 K / Max: 100.0 K
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 3710 pixel / Digitization - Dimensions - Height: 3838 pixel / Digitization - Frames/image: 1-50 / Number grids imaged: 2 / Number real images: 4210 / Average exposure time: 7.0 sec. / Average electron dose: 84.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 354752
Startup modelType of model: EMDB MAP
EMDB ID:
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 1.4)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: FREALIGN
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: FREALIGN / Number images used: 354752

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: FLEXIBLE FIT
Output model

PDB-6bhu:
Cryo-EM structure of ATP-bound, outward-facing bovine multidrug resistance protein 1 (MRP1)

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