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- PDB-8zbs: Cryo-EM structure of nanodisc-reconstituted wildtype human MRP4 (... -

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Entry
Database: PDB / ID: 8zbs
TitleCryo-EM structure of nanodisc-reconstituted wildtype human MRP4 (in complex with vincristine)
ComponentsATP-binding cassette sub-family C member 4
KeywordsMEMBRANE PROTEIN / ATP-binding cassette sub-family C member 4 / Multidrug resistance proteins (MRPs) / multidrug-resistance (MDR) / TRANSPORT 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 / prostaglandin transport / leukotriene transport / prostaglandin transmembrane transporter activity ...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 / prostaglandin transport / leukotriene transport / prostaglandin transmembrane transporter activity / urate transport / glutathione transmembrane transporter activity / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate 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 / 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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / vincristine / ATP-binding cassette sub-family C member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.96 Å
AuthorsXie, Z. / Long, F.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 9, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-binding cassette sub-family C member 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)154,0906
Polymers152,2041
Non-polymers1,8865
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein ATP-binding cassette sub-family C member 4 / MRP/cMOAT-related ABC transporter / Multi-specific organic anion transporter B / MOAT-B / Multidrug ...MRP/cMOAT-related ABC transporter / Multi-specific organic anion transporter B / MOAT-B / Multidrug resistance-associated protein 4


Mass: 152203.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCC4, MOATB, MRP4 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O15439, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate, ABC-type xenobiotic transporter, ABC-type ...References: UniProt: O15439, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate, ABC-type xenobiotic transporter, ABC-type glutathione-S-conjugate transporter
#2: Chemical ChemComp-R1Q / vincristine


Mass: 824.958 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C46H56N4O10 / Comment: medication, chemotherapy*YM
#3: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
Has ligand of interestY
Has protein modificationN

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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: Cryo-EM structure of nanodisc-reconstituted wildtype human MRP4 (in complex with vincristine)
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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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 FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
2EPUVersion 3.2.0.4776RELimage acquisition
9PHENIX1.20.1-4487model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.96 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 209295 / Symmetry type: POINT
Atomic model buildingSource name: AlphaFold / Type: in silico model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 111.6 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002310070
ELECTRON MICROSCOPYf_angle_d0.531813676
ELECTRON MICROSCOPYf_chiral_restr0.03891584
ELECTRON MICROSCOPYf_plane_restr0.0031680
ELECTRON MICROSCOPYf_dihedral_angle_d6.36181390

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