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- PDB-8sx7: Bovine multidrug resistance protein 4 (MRP4) bound to DHEA-S in M... -

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Basic information

Entry
Database: PDB / ID: 8sx7
TitleBovine multidrug resistance protein 4 (MRP4) bound to DHEA-S in MSP lipid nanodisc
ComponentsMultidrug resistance-associated protein 4
KeywordsTRANSPORT PROTEIN / ABC transporter / multidrug resistance-associated protein / membrane protein
Function / homology
Function and homology information


Platelet degranulation / Paracetamol ADME / Azathioprine ADME / ABC-family proteins mediated transport / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / transmembrane transport / ATP hydrolysis activity / ATP binding / 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
17-oxoandrost-5-en-3beta-yl hydrogen sulfate / ATP binding cassette subfamily C member 4
Similarity search - Component
Biological speciesBos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsPourmal, S. / Stroud, R.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM24485 United States
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structural basis of prostaglandin efflux by MRP4.
Authors: Sergei Pourmal / Evan Green / Ruchika Bajaj / Ilan E Chemmama / Giselle M Knudsen / Meghna Gupta / Andrej Sali / Yifan Cheng / Charles S Craik / Deanna L Kroetz / Robert M Stroud /
Abstract: Multidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a group of signaling molecules ...Multidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a group of signaling molecules derived from unsaturated fatty acids. To better understand the basis of the substrate selectivity of MRP4, we used cryogenic-electron microscopy to determine six structures of nanodisc-reconstituted MRP4 at various stages throughout its transport cycle. Substrate-bound structures of MRP4 in complex with PGE, PGE and the sulfonated-sterol DHEA-S reveal a common binding site that accommodates a diverse set of organic anions and suggest an allosteric mechanism for substrate-induced enhancement of MRP4 ATPase activity. Our structure of a catalytically compromised MRP4 mutant bound to ATP-Mg is outward-occluded, a conformation previously unobserved in the MRP subfamily and consistent with an alternating-access transport mechanism. Our study provides insights into the endogenous function of this versatile efflux transporter and establishes a basis for MRP4-targeted drug design.
History
DepositionMay 20, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 17, 2024Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Multidrug resistance-associated protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)149,9562
Polymers149,5871
Non-polymers3681
Water543
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Multidrug resistance-associated protein 4


Mass: 149587.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: LOC515333 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: F1MUC1
#2: Chemical ChemComp-ZWY / 17-oxoandrost-5-en-3beta-yl hydrogen sulfate / Dehydroepiandrosterone sulfate / DHEA sulfate / DHEA-S


Mass: 368.488 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H28O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O
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: Bovine multidrug resistance protein 4 (MRP4) bound to DHEA-S in MSP lipid nanodisc
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.15 MDa / Experimental value: NO
Source (natural)Organism: Bos taurus (domestic cattle)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
Details: 20 mM Tris-HCL, 150 mM NaCl, 1 mM TCEP, 200 uM DHEA-S, 2% DMSO
SpecimenConc.: 0.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Multidrug resistance-associated protein (MRP4) in MSP lipid nanodisc
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 66 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 6875
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansWidth: 5760 / Height: 4092

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategoryDetails
2SerialEM3.8image acquisitionStable
4cryoSPARC3.2CTF correction
8PHENIXmodel refinement
13cryoSPARC3.23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 5330431
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 360511 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049725
ELECTRON MICROSCOPYf_angle_d0.67513190
ELECTRON MICROSCOPYf_dihedral_angle_d12.4613547
ELECTRON MICROSCOPYf_chiral_restr0.0491523
ELECTRON MICROSCOPYf_plane_restr0.0061642

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