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- PDB-9c2i: Inward-facing, ligand-free Multidrug Resistance-associated protei... -

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Basic information

Entry
Database: PDB / ID: 9c2i
TitleInward-facing, ligand-free Multidrug Resistance-associated protein 2 (MRP2)
ComponentsATP-binding cassette sub-family C member 2
KeywordsTRANSPORT PROTEIN / ABC Transporter / Multidrug Resistance / Regulatory Domain / Autoinhibition
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 transmembrane transport / xenobiotic transport across blood-brain barrier / : / 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
CHOLESTEROL / Unknown ligand / ATP-binding cassette sub-family C member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.62 Å
AuthorsKoide, E. / Chen, J.
Funding support United States, 1items
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 31, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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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 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)182,64714
Polymers174,3921
Non-polymers8,25413
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 2 / Canalicular multidrug resistance protein / Canalicular multispecific organic anion transporter 1 / ...Canalicular multidrug resistance protein / Canalicular multispecific organic anion transporter 1 / Multidrug resistance-associated protein 2


Mass: 174392.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCC2, CMOAT, CMOAT1, CMRP, MRP2 / Production host: Homo sapiens (human)
References: UniProt: Q92887, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate, ABC-type xenobiotic transporter, ABC-type ...References: UniProt: Q92887, 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-UNL / UNKNOWN LIGAND


Mass: 790.145 Da / Num. of mol.: 8 / Source method: obtained synthetically
#3: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C27H46O
Has ligand of interestN
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: MRP2 in inward-facing, R-domain engaged conformation / Type: CELL
Details: detergent-solubilized MRP2 purified in the absence of ligand. Lipids and cholesterols were identified bound to the protein.
Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human) / Cellular location: apical cell membrane
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293 GnTl negative
Buffer solutionpH: 8
Details: Digitonin is solubilized overnight. Prior to use, it is filtered using a 0.22 uM filter.
Buffer component
IDConc.NameFormulaBuffer-ID
10.06 %DigitoninDigitonin1
2150 mMsodium chlorideNaCl1
350 mMTrisTris1
42 mMmagnesium chlorideMgCl21
52 mMDTTDTT1
SpecimenConc.: 4.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295.15 K

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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: 2500 nm / Nominal defocus min: 800 nm / Cs: 0 mm
Image recordingElectron dose: 65 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.21.1_5286 / Classification: refinement
EM softwareName: PHENIX / Version: 1.21.1_5286 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.62 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 113359 / Num. of class averages: 1 / Symmetry type: POINT
RefinementCross valid method: NONE

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