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- EMDB-39910: Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q... -

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Basic information

Entry
Database: EMDB / ID: EMD-39910
TitleCryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q mutation (in complex with 5-Fluorouracil)
Map data
Sample
  • Complex: Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q mutation (in complex with 5-Fluorouracil)
    • Protein or peptide: ATP-binding cassette sub-family C member 4
  • Ligand: 5-FLUOROURACIL
  • Ligand: MAGNESIUM ION
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
KeywordsATP-binding cassette sub-family C member 4 / Multidrug resistance proteins (MRPs) / multidrug-resistance (MDR) / TRANSPORT PROTEIN / membrane protein
Function / homology
Function and homology information


15-hydroxyprostaglandin dehydrogenase (NAD+) activity / purine nucleotide transmembrane transporter activity / cAMP transport / guanine nucleotide transmembrane transporter activity / ABC-type bile acid transporter activity / platelet dense granule membrane / platelet degranulation / leukotriene transport / prostaglandin transport / ABC-type glutathione-S-conjugate transporter ...15-hydroxyprostaglandin dehydrogenase (NAD+) activity / purine nucleotide transmembrane transporter activity / cAMP transport / guanine nucleotide transmembrane transporter activity / ABC-type bile acid transporter activity / platelet dense granule membrane / platelet degranulation / leukotriene transport / prostaglandin transport / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / urate transport / glutathione transmembrane transporter activity / prostaglandin transmembrane transporter activity / urate transmembrane transporter activity / ATPase-coupled inorganic anion transmembrane transporter activity / external side of apical plasma membrane / xenobiotic transmembrane transport / prostaglandin secretion / export across plasma membrane / Paracetamol ADME / ABC-type xenobiotic transporter / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / Azathioprine ADME / ABC-type xenobiotic transporter activity / bile acid and bile salt transport / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / cilium assembly / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / transport across blood-brain barrier / xenobiotic metabolic process / ABC-family proteins mediated transport / transmembrane transport / Platelet degranulation / basolateral plasma membrane / apical plasma membrane / intracellular membrane-bounded organelle / nucleolus / Golgi apparatus / ATP hydrolysis activity / ATP binding / membrane / plasma membrane
Similarity search - Function
ATP-binding cassette sub-family C member 4 / : / : / 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 ...ATP-binding cassette sub-family C member 4 / : / : / 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 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsXie Z / Long F
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2021YFA0909500 China
CitationJournal: Cell Rep / Year: 2025
Title: Structural basis for the reversal of human MRP4-mediated multidrug resistance by lapatinib.
Authors: Zhipeng Xie / Jiaxiang Lv / Wei Huang / Zhikun Wu / Rongli Zhu / Zixin Deng / Feng Long /
Abstract: Multidrug resistance proteins (MRPs) are one of the major mechanisms for developing cancer drug resistance. Human MRP4 (hMRP4) plays an important role in various chemotherapy-resistant cancers. Here, ...Multidrug resistance proteins (MRPs) are one of the major mechanisms for developing cancer drug resistance. Human MRP4 (hMRP4) plays an important role in various chemotherapy-resistant cancers. Here, we show hMRP4 mediates the resistance of a broad spectrum of antitumor reagents in the cultured tumor cells, among which the cell resistance to vincristine and 5-fluorouracil is rescued by supplementing a tyrosinase inhibitor, lapatinib. The cryoelectron microscopy (cryo-EM) structures of hMRP4 in the substrate- or inhibitor-bound form are determined. Although lapatinib shares partial binding sites with vincristine and 5-fluorouracil using a similar set of crucial residues located in the central cavity of hMRP4, the high binding affinity of lapatinib and its unique binding mode with transmembrane helices TM2 and TM12 inside the pathway tunnel prohibit hMRP4 from structural transition between intermediate states during drug translocation. This study provides mechanistic insights into the therapeutical potential of lapatinib in combating hMRP4-mediated MDR.
History
DepositionApr 27, 2024-
Header (metadata) releaseApr 9, 2025-
Map releaseApr 9, 2025-
UpdateApr 9, 2025-
Current statusApr 9, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_39910.png

Downloads & links

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Map

FileDownload / File: emd_39910.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.94 Å/pix.
x 256 pix.
= 240.64 Å		0.94 Å/pix.
x 256 pix.
= 240.64 Å		0.94 Å/pix.
x 256 pix.
= 240.64 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.94 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.45193213 - 0.65418804
Average (Standard dev.)0.00084230764 (±0.01977396)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 240.64 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_39910_msk_1.map
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Half map: #2

Fileemd_39910_half_map_1.map
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Half map: #1

Fileemd_39910_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q...

EntireName: Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q mutation (in complex with 5-Fluorouracil)
Components
  • Complex: Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q mutation (in complex with 5-Fluorouracil)
    • Protein or peptide: ATP-binding cassette sub-family C member 4
  • Ligand: 5-FLUOROURACIL
  • Ligand: MAGNESIUM ION
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE

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Supramolecule #1: Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q...

SupramoleculeName: Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q mutation (in complex with 5-Fluorouracil)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: ATP-binding cassette sub-family C member 4

MacromoleculeName: ATP-binding cassette sub-family C member 4 / 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: 152.202562 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHHHH HMLPVYQEVK PNPLQDANLC SRVFFWWLNP LFKIGHKRRL EEDDMYSVLP EDRSQHLGEE LQGFWDKEVL RAENDAQKP SLTRAIIKCY WKSYLVLGIF TLIEESAKVI QPIFLGKIIN YFENYDPMDS VALNTAYAYA TVLTFCTLIL A ILHHLYFY ...String:
MHHHHHHHHH HMLPVYQEVK PNPLQDANLC SRVFFWWLNP LFKIGHKRRL EEDDMYSVLP EDRSQHLGEE LQGFWDKEVL RAENDAQKP SLTRAIIKCY WKSYLVLGIF TLIEESAKVI QPIFLGKIIN YFENYDPMDS VALNTAYAYA TVLTFCTLIL A ILHHLYFY HVQCAGMRLR VAMCHMIYRK ALRLSNMAMG KTTTGQIVNL LSNDVNKFDQ VTVFLHFLWA GPLQAIAVTA LL WMEIGIS CLAGMAVLII LLPLQSCFGK LFSSLRSKTA TFTDARIRTM NEVITGIRII KMYAWEKSFS NLITNLRKKE ISK ILRSSC LRGMNLASFF SASKIIVFVT FTTYVLLGSV ITASRVFVAV TLYGAVRLTV TLFFPSAIER VSEAIVSIRR IQTF LLLDE ISQRNRQLPS DGKKMVHVQD FTAFWDKASE TPTLQGLSFT VRPGELLAVV GPVGAGKSSL LSAVLGELAP SHGLV SVHG RIAYVSQQPW VFSGTLRSNI LFGKKYEKER YEKVIKACAL KKDLQLLEDG DLTVIGDRGT TLSGGQKARV NLARAV YQD ADIYLLDDPL SAVDAEVSRH LFELCICQIL HEKITILVTH QLQYLKAASQ ILILKDGKMV QKGTYTEFLK SGIDFGS LL KKDNEESEQP PVPGTPTLRN RTFSESSVWS QQSSRPSLKD GALESQDTEN VPVTLSEENR SEGKVGFQAY KNYFRAGA H WIVFIFLILL NTAAQVAYVL QDWWLSYWAN KQSMLNVTVN GGGNVTEKLD LNWYLGIYSG LTVATVLFGI ARSLLVFYV LVNSSQTLHN KMFESILKAP VLFFDRNPIG RILNRFSKDI GHLDDLLPLT FLDFIQTLLQ VVGVVSVAVA VIPWIAIPLV PLGIIFIFL RRYFLETSRD VKRLESTTRS PVFSHLSSSL QGLWTIRAYK AEERCQELFD AHQDLHSEAW FLFLTTSRWF A VRLDAICA MFVIIVAFGS LILAKTLDAG QVGLALSYAL TLMGMFQWCV RQSAEVENMM ISVERVIEYT DLEKEAPWEY QK RPPPAWP HEGVIIFDNV NFMYSPGGPL VLKHLTALIK SQEKVGIVGR TGAGKSSLIS ALFRLSEPEG KIWIDKILTT EIG LHDLRK KMSIIPQEPV LFTGTMRKNL DPFNEHTDEE LWNALQEVQL KETIEDLPGK MDTELAESGS NFSVGQRQLV CLAR AILRK NQILIIDQAT ANVDPRTDEL IQKKIREKFA HCTVLTIAHR LNTIIDSDKI MVLDSGRLKE YDEPYVLLQN KESLF YKMV QQLGKAEAAA LTETAKQVYF KRNYPHIGHT DHMVTNTSNG QPSTLTIFET ALDYKDDDDK

UniProtKB: ATP-binding cassette sub-family C member 4

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Macromolecule #2: 5-FLUOROURACIL

MacromoleculeName: 5-FLUOROURACIL / type: ligand / ID: 2 / Number of copies: 1 / Formula: URF
Molecular weightTheoretical: 130.077 Da
Chemical component information

ChemComp-URF:
5-FLUOROURACIL / medication, chemotherapy*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: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 4 / 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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration3 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 50 sec.
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
SoftwareName: EPU (ver. Version 3.2.0.4776REL)
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 128199
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
Output model

PDB-8zbt:
Cryo-EM structure of nanodisc-reconstituted human MRP4 withE1202Q mutation (in complex with 5-Fluorouracil)

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