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- EMDB-8560: Cryo-EM structure of bovine multidrug resistance protein 1 (MRP1)... -

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Basic information

Entry
Database: EMDB / ID: EMD-8560
TitleCryo-EM structure of bovine multidrug resistance protein 1 (MRP1) bound to leukotriene C4
Map dataFull map translated into unit cell used for reciprocal space refinement, sharpened with a B-factor of -100 A^2 and a resolution cutoff of 3.34 A
Sample
  • Complex: bovine multidrug resistance protein 1 (MRP1) complexed with leukotriene C4
    • Protein or peptide: bovine multidrug resistance protein 1 (MRP1),Multidrug resistance-associated protein 1
  • Ligand: (5~{S},6~{R},7~{E},9~{E},11~{Z},14~{Z})-6-[(2~{R})-2-[[(4~{S})-4-azanyl-5-oxidanyl-5-oxidanylidene-pentanoyl]amino]-3-( 2-hydroxy-2-oxoethylamino)-3-oxidanylidene-propyl]sulfanyl-5-oxidanyl-icosa-7,9,11,14-tetraenoic acid
KeywordsABC transporter / multidrug resistance / leukotriene C4 / LTC4 / PROTEIN TRANSPORT
Function / homology
Function and homology information


Sphingolipid de novo biosynthesis / Heme degradation / Synthesis of Leukotrienes (LT) and Eoxins (EX) / cyclic nucleotide transport / Transport of RCbl within the body / Paracetamol ADME / leukotriene transport / glutathione transmembrane transport / glutathione transmembrane transporter activity / ABC-family proteins mediated transport ...Sphingolipid de novo biosynthesis / Heme degradation / Synthesis of Leukotrienes (LT) and Eoxins (EX) / cyclic nucleotide transport / Transport of RCbl within the body / Paracetamol ADME / leukotriene transport / glutathione transmembrane transport / glutathione transmembrane transporter activity / ABC-family proteins mediated transport / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / Cytoprotection by HMOX1 / ABC-type xenobiotic transporter / ABC-type xenobiotic transporter activity / lipid transport / xenobiotic 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 ...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: 3.34 Å
AuthorsJohnson ZL / Chen J
Funding support United States, 3 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
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, 2017-
Header (metadata) releaseFeb 22, 2017-
Map releaseFeb 22, 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: 1.6
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 1.6
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-5uja
  • Surface level: 1.6
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8560.png

Downloads & links

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Map

FileDownload / File: emd_8560.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map translated into unit cell used for reciprocal space refinement, sharpened with a B-factor of -100 A^2 and a resolution cutoff of 3.34 A
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesY (Sec.)X (Row.)Z (Col.)
0.26 Å/pix.
x 384 pix.
= 98.999 Å		0.38 Å/pix.
x 384 pix.
= 146.001 Å		0.28 Å/pix.
x 384 pix.
= 107.002 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX: 0.38021 Å / Y: 0.25781 Å / Z: 0.27865 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.6 / Movie #1: 1.6
Minimum - Maximum-4.154357 - 5.2137184
Average (Standard dev.)0.21231677 (±0.61837626)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZXY
Origin000
Dimensions384384384
Spacing384384384
CellA: 146.00064 Å / B: 98.99904 Å / C: 107.001595 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.38021093750.257809895833330.27865104166667
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z146.00198.999107.002
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ384384384
MAP C/R/S312
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-4.1545.2140.212

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Supplemental data

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Additional map: Full map translated into unit cell used for...

Fileemd_8560_additional.map
AnnotationFull map translated into unit cell used for reciprocal space refinement, unsharpened
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2 translated into unit cell used...

Fileemd_8560_half_map_1.map
AnnotationHalf map 2 translated into unit cell used for reciprocal space refinement, scaled to PDB coordinates, unsharpened
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1 translated into unit cell used...

Fileemd_8560_half_map_2.map
AnnotationHalf map 1 translated into unit cell used for reciprocal space refinement, scaled to PDB coordinates, unsharpened
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : bovine multidrug resistance protein 1 (MRP1) complexed with leuko...

EntireName: bovine multidrug resistance protein 1 (MRP1) complexed with leukotriene C4
Components
  • Complex: bovine multidrug resistance protein 1 (MRP1) complexed with leukotriene C4
    • Protein or peptide: bovine multidrug resistance protein 1 (MRP1),Multidrug resistance-associated protein 1
  • Ligand: (5~{S},6~{R},7~{E},9~{E},11~{Z},14~{Z})-6-[(2~{R})-2-[[(4~{S})-4-azanyl-5-oxidanyl-5-oxidanylidene-pentanoyl]amino]-3-( 2-hydroxy-2-oxoethylamino)-3-oxidanylidene-propyl]sulfanyl-5-oxidanyl-icosa-7,9,11,14-tetraenoic acid

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Supramolecule #1: bovine multidrug resistance protein 1 (MRP1) complexed with leuko...

SupramoleculeName: bovine multidrug resistance protein 1 (MRP1) complexed with leukotriene C4
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: bovine multidrug resistance protein 1 (MRP1),Multidrug resistance...

MacromoleculeName: bovine multidrug resistance protein 1 (MRP1),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: 159.701922 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)(UNK)(UNK)(UNK) (UNK)(UNK)PNPCPESS ASFLSRI TF WWITGMMVQG YRQPLESTDL WSLNKEDTSE QVVPVLVKNW KKECAKSRKQ PVKIVYSSKD PAKPKGSSKV DVNEEAEA L IVKCPQKERD PSLFKVLYKT FGPYFLMSFL FKAVHDLMMF AGPEILKLLI NFVNDKKAPE WQGYFYTALL FISACLQTL VLHQYFHICF VSGMRIKTAV IGAVYRKALV ITNAARKSST VGEIVNLMSV DAQRFMDLAT YINMIWSAPL QVILALYLLW LNLGPSVLA GVAVMVLMVP LNAVMAMKTK TYQVAHMKSK DNRIKLMNEI LNGIKVLKLY AWELAFKDKV LAIRQEELKV L KKSAYLAA VGTFTWVCTP FLVALSTFAV YVTVDENNIL DAQKAFVSLA LFNILRFPLN ILPMVISSIV QASVSLKRLR VF LSHEDLD PDSIQRRPIK DAGATNSITV KNATFTWARN DPPTLHGITF SVPEGSLVAV VGQVGCGKSS LLSALLAEMD KVE GHVTVK GSVAYVPQQA WIQNISLREN ILFGRQLQER YYKAVVEACA LLPDLEILPS GDRTEIGEKG VNLSGGQKQR VSLA RAVYC DSDVYLLDDP LSAVDAHVGK HIFENVIGPK GLLKNKTRLL VTHAISYLPQ MDVIIVMSGG KISEMGSYQE LLARD GAFA EFLRTYASAE QEQGQPEDGL AGVGGPGKEV KQMENGMLVT DTAGKQMQRQ LSSSSSYSRD VSQHHTSTAE LRKPGP TEE TWKLVEADKA QTGQVKLSVY WDYMKAIGLF ISFLSIFLFL CNHVASLVSN YWLSLWTDDP IVNGTQEHTQ VRLSVYG AL GISQGITVFG YSMAVSIGGI FASRRLHLDL LHNVLRSPIS FFERTPSGNL VNRFSKELDT VDSMIPQVIK MFMGSLFN V IGACIIILLA TPMAAVIIPP LGLIYFFVQR FYVASSRQLK RLESVSRSPV YSHFNETLLG VSVIRAFEEQ ERFIRQSDL KVDENQKAYY PSIVANRWLA VRLECVGNCI VLFASLFAVI SRHSLSAGLV GLSVSYSLQV TTYLNWLVRM SSEMETNIVA VERLKEYSE TEKEAPWQIQ DMAPPKDWPQ VGRVEFRDYG LRYREDLDLV LKHINVTIDG GEKVGIVGRT GAGKSSLTLG L FRIKESAE GEIIIDDINI AKIGLHDLRF KITIIPQDPV LFSGSLRMNL DPFSQYSDEE VWTSLELAHL KGFVSALPDK LN HECAEGG ENLSVGQRQL VCLARALLRK TKILVLDEAT AAVDLETDDL IQSTIRTQFD DCTVLTIAHR LNTIMDYTRV IVL DKGEIQ EWGSPSDLLQ QRGLFYSMAK DSGLVSNSLE VLFQ

UniProtKB: Multidrug resistance-associated protein 1

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Macromolecule #2: (5~{S},6~{R},7~{E},9~{E},11~{Z},14~{Z})-6-[(2~{R})-2-[[(4~{S})-4-...

MacromoleculeName: (5~{S},6~{R},7~{E},9~{E},11~{Z},14~{Z})-6-[(2~{R})-2-[[(4~{S})-4-azanyl-5-oxidanyl-5-oxidanylidene-pentanoyl]amino]-3-( 2-hydroxy-2-oxoethylamino)-3-oxidanylidene-propyl]sulfanyl-5-oxidanyl- ...Name: (5~{S},6~{R},7~{E},9~{E},11~{Z},14~{Z})-6-[(2~{R})-2-[[(4~{S})-4-azanyl-5-oxidanyl-5-oxidanylidene-pentanoyl]amino]-3-( 2-hydroxy-2-oxoethylamino)-3-oxidanylidene-propyl]sulfanyl-5-oxidanyl-icosa-7,9,11,14-tetraenoic acid
type: ligand / ID: 2 / Number of copies: 1 / Formula: LTX
Molecular weightTheoretical: 625.774 Da

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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

Concentration4.65 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
40.0 uMLeukotriene C4
2.5 %DMSO
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
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: 1 / Number real images: 2302 / Average exposure time: 7.0 sec. / Average electron dose: 84.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / 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
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 203732
Startup modelType of model: OTHER / Details: Generated from ISAC and VIPER in the SPARX suite
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: FREALIGN / Number images used: 203732
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 1.4)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: FREALIGN

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: AB INITIO MODEL
Output model

PDB-5uja:
Cryo-EM structure of bovine multidrug resistance protein 1 (MRP1) bound to leukotriene C4

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