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- EMDB-44911: Outward-facing, ATP-bound Multidrug Resistance-associated Protein... -

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Basic information

Entry
Database: EMDB / ID: EMD-44911
TitleOutward-facing, ATP-bound Multidrug Resistance-associated Protein 2 (MRP2) (E1462Q)
Map datacryo-EM reconstruction of MRP2(E1462Q) NBD-dimerized, outward facing conformation
Sample
  • Cell: MRP2(E1462Q) in outward-facing, NBD-dimerized conformation
    • Protein or peptide: ATP-binding cassette sub-family C member 2
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: UNKNOWN LIGAND
  • Ligand: CHOLESTEROL
KeywordsABC transporter / Multidrug resistance / regulatory domain / nucleotide binding / TRANSPORT PROTEIN
Function / homology
Function and homology information


Defective ABCC2 causes DJS / bilirubin transmembrane transporter activity / bilirubin transport / xenobiotic export from cell / leukotriene transport / ABC-type glutathione S-conjugate transporter activity / ABC-type glutathione-S-conjugate transporter / : / heme catabolic process / Atorvastatin ADME ...Defective ABCC2 causes DJS / bilirubin transmembrane transporter activity / bilirubin transport / xenobiotic export from cell / leukotriene transport / ABC-type glutathione S-conjugate transporter activity / ABC-type glutathione-S-conjugate transporter / : / heme catabolic process / Atorvastatin ADME / xenobiotic transport across blood-brain barrier / xenobiotic transmembrane transport / intercellular canaliculus / : / transepithelial transport / Paracetamol ADME / ABC-type xenobiotic transporter / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / ABC-type xenobiotic transporter activity / Heme degradation / bile acid and bile salt transport / Aspirin ADME / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / transport across blood-brain barrier / xenobiotic metabolic process / ABC-family proteins mediated transport / transmembrane transport / apical plasma membrane / negative regulation of gene expression / cell surface / ATP hydrolysis activity / ATP binding / plasma membrane
Similarity search - Function
Multi drug resistance-associated protein / : / ABC transporter TMD0 domain / : / 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. ...Multi drug resistance-associated protein / : / ABC transporter TMD0 domain / : / 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
ATP-binding cassette sub-family C member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsKoide E / Chen J
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis for the transport and regulation mechanism of the multidrug resistance-associated protein 2.
Authors: Eriko Koide / Harlan L Pietz / Jean Beltran / Jue Chen /
Abstract: Multidrug resistance-associated protein 2 (MRP2) is an ATP-powered exporter important for maintaining liver homeostasis and a potential contributor to chemotherapeutic resistance. Using cryogenic ...Multidrug resistance-associated protein 2 (MRP2) is an ATP-powered exporter important for maintaining liver homeostasis and a potential contributor to chemotherapeutic resistance. Using cryogenic electron microscopy (cryo-EM), we determine the structures of human MRP2 in three conformational states: an autoinhibited state, a substrate-bound pre-translocation state, and an ATP-bound post-translocation state. In the autoinhibited state, the cytosolic regulatory (R) domain plugs into the transmembrane substrate-binding site and extends into the cytosol to form a composite ATP-binding site at the surface of nucleotide-binding domain 2. Substrate displaces the R domain, permitting conformational changes necessary for transport. These observations suggest that the R domain functions as a selectivity gauge, where only at sufficiently high concentrations can the substrate effectively initiate transport. Comparative structural analyzes of MRP2 bound to various substrates, as determined in this study and others, reveal how MRP2 recognizes a diverse array of compounds, supporting its role in multidrug resistance.
History
DepositionMay 17, 2024-
Header (metadata) releaseDec 18, 2024-
Map releaseDec 18, 2024-
UpdateFeb 12, 2025-
Current statusFeb 12, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44911.png

Downloads & links

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Map

FileDownload / File: emd_44911.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo-EM reconstruction of MRP2(E1462Q) NBD-dimerized, outward facing conformation
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.68 Å/pix.
x 360 pix.
= 243.36 Å		0.68 Å/pix.
x 360 pix.
= 243.36 Å		0.68 Å/pix.
x 360 pix.
= 243.36 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.676 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.062
Minimum - Maximum-0.2670289 - 0.48567238
Average (Standard dev.)0.00083391287 (±0.0136093665)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 243.36 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A

Fileemd_44911_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_44911_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : MRP2(E1462Q) in outward-facing, NBD-dimerized conformation

EntireName: MRP2(E1462Q) in outward-facing, NBD-dimerized conformation
Components
  • Cell: MRP2(E1462Q) in outward-facing, NBD-dimerized conformation
    • Protein or peptide: ATP-binding cassette sub-family C member 2
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: UNKNOWN LIGAND
  • Ligand: CHOLESTEROL

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Supramolecule #1: MRP2(E1462Q) in outward-facing, NBD-dimerized conformation

SupramoleculeName: MRP2(E1462Q) in outward-facing, NBD-dimerized conformation
type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: detergent-solubilized MRP2(E1462Q) bound to ATP and magnesium. Lipids and cholesterols were also identified bound to the protein.
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: ATP-binding cassette sub-family C member 2

MacromoleculeName: ATP-binding cassette sub-family C member 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 174.391359 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MLEKFCNSTF WNSSFLDSPE ADLPLCFEQT VLVWIPLGYL WLLAPWQLLH VYKSRTKRSS TTKLYLAKQV FVGFLLILAA IELALVLTE DSGQATVPAV RYTNPSLYLG TWLLVLLIQY SRQWCVQKNS WFLSLFWILS ILCGTFQFQT LIRTLLQGDN S NLAYSCLF ...String:
MLEKFCNSTF WNSSFLDSPE ADLPLCFEQT VLVWIPLGYL WLLAPWQLLH VYKSRTKRSS TTKLYLAKQV FVGFLLILAA IELALVLTE DSGQATVPAV RYTNPSLYLG TWLLVLLIQY SRQWCVQKNS WFLSLFWILS ILCGTFQFQT LIRTLLQGDN S NLAYSCLF FISYGFQILI LIFSAFSENN ESSNNPSSIA SFLSSITYSW YDSIILKGYK RPLTLEDVWE VDEEMKTKTL VS KFETHMK RELQKARRAL QRRQEKSSQQ NSGARLPGLN KNQSQSQDAL VLEDVEKKKK KSGTKKDVPK SWLMKALFKT FYM VLLKSF LLKLVNDIFT FVSPQLLKLL ISFASDRDTY LWIGYLCAIL LFTAALIQSF CLQCYFQLCF KLGVKVRTAI MASV YKKAL TLSNLARKEY TVGETVNLMS VDAQKLMDVT NFMHMLWSSV LQIVLSIFFL WRELGPSVLA GVGVMVLVIP INAIL STKS KTIQVKNMKN KDKRLKIMNE ILSGIKILKY FAWEPSFRDQ VQNLRKKELK NLLAFSQLQC VVIFVFQLTP VLVSVV TFS VYVLVDSNNI LDAQKAFTSI TLFNILRFPL SMLPMMISSM LQASVSTERL EKYLGGDDLD TSAIRHDCNF DKAMQFS EA SFTWEHDSEA TVRDVNLDIM AGQLVAVIGP VGSGKSSLIS AMLGEMENVH GHITIKGTTA YVPQQSWIQN GTIKDNIL F GTEFNEKRYQ QVLEACALLP DLEMLPGGDL AEIGEKGINL SGGQKQRISL ARATYQNLDI YLLDDPLSAV DAHVGKHIF NKVLGPNGLL KGKTRLLVTH SMHFLPQVDE IVVLGNGTIV EKGSYSALLA KKGEFAKNLK TFLRHTGPEE EATVHDGSEE EDDDYGLIS SVEEIPEDAA SITMRRENSF RRTLSRSSRS NGRHLKSLRN SLKTRNVNSL KEDEELVKGQ KLIKKEFIET G KVKFSIYL EYLQAIGLFS IFFIILAFVM NSVAFIGSNL WLSAWTSDSK IFNSTDYPAS QRDMRVGVYG ALGLAQGIFV FI AHFWSAF GFVHASNILH KQLLNNILRA PMRFFDTTPT GRIVNRFAGD ISTVDDTLPQ SLRSWITCFL GIISTLVMIC MAT PVFTII VIPLGIIYVS VQMFYVSTSR QLRRLDSVTR SPIYSHFSET VSGLPVIRAF EHQQRFLKHN EVRIDTNQKC VFSW ITSNR WLAIRLELVG NLTVFFSALM MVIYRDTLSG DTVGFVLSNA LNITQTLNWL VRMTSEIETN IVAVERITEY TKVEN EAPW VTDKRPPPDW PSKGKIQFNN YQVRYRPELD LVLRGITCDI GSMEKIGVVG RTGAGKSSLT NCLFRILEAA GGQIII DGV DIASIGLHDL REKLTIIPQD PILFSGSLRM NLDPFNNYSD EEIWKALELA HLKSFVASLQ LGLSHEVTEA GGNLSIG QR QLLCLGRALL RKSKILVLDQ ATAAVDLETD NLIQTTIQNE FAHCTVITIA HRLHTIMDSD KVMVLDNGKI IECGSPEE L LQIPGPFYFM AKEAGIENVN STKF

UniProtKB: ATP-binding cassette sub-family C member 2

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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

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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: UNKNOWN LIGAND

MacromoleculeName: UNKNOWN LIGAND / type: ligand / ID: 4 / Number of copies: 3 / Formula: UNL
Molecular weightTheoretical: 790.145 Da
Chemical component information


ChemComp, No image

ChemComp-UNL:
Unknown ligand

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 5 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
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

Concentration4.5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
0.06 %DigitoninDigitonin
150.0 mMNaClsodium chloride
50.0 mMTrisTris
2.0 mMMgCl2magnesium chloride
2.0 mMDTTDTT

Details: Digitonin is solubilized overnight. Prior to use, it is filtered using a 0.22 uM filter.
GridModel: Quantifoil R0.6/1 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 12 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 0.0 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 28003
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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