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- PDB-8jx7: Cryo-EM structure of human ABC transporter ABCC2 -

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Basic information

Entry
Database: PDB / ID: 8jx7
TitleCryo-EM structure of human ABC transporter ABCC2
ComponentsATP-binding cassette sub-family C member 2
KeywordsTRANSPORT PROTEIN / ATP-dependent transporter / conjugated organic anions transporter / ATP hydrolyzes / bilirubin / ABC transporter
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 / ABC-type glutathione S-conjugate transporter activity / ATPase-coupled inorganic anion transmembrane transporter activity / heme catabolic process / xenobiotic transmembrane transport ...Defective ABCC2 causes DJS / bilirubin transmembrane transporter activity / bilirubin transport / xenobiotic export from cell / leukotriene transport / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / ATPase-coupled inorganic anion transmembrane transporter activity / heme catabolic process / xenobiotic transmembrane transport / Atorvastatin ADME / organic anion transmembrane transporter activity / xenobiotic transport across blood-brain barrier / ABC-type xenobiotic transporter / intercellular canaliculus / Paracetamol ADME / transepithelial transport / bile acid and bile salt transport / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / ABC-type xenobiotic transporter activity / Heme degradation / Aspirin ADME / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / 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 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. ...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
ATP-binding cassette sub-family C member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsMao, Y.X. / Chen, Z.P. / Wang, L. / Hou, W.T. / Chen, Y.X. / Zhou, C.Z.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDB37020202 China
CitationJournal: Nat Commun / Year: 2024
Title: Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain.
Authors: Yao-Xu Mao / Zhi-Peng Chen / Liang Wang / Jie Wang / Cong-Zhao Zhou / Wen-Tao Hou / Yuxing Chen /
Abstract: Bilirubin is mainly generated from the breakdown of heme when red blood cells reach the end of their lifespan. Accumulation of bilirubin in human body usually leads to various disorders, including ...Bilirubin is mainly generated from the breakdown of heme when red blood cells reach the end of their lifespan. Accumulation of bilirubin in human body usually leads to various disorders, including jaundice and liver disease. Bilirubin is conjugated in hepatocytes and excreted to bile duct via the ATP-binding cassette transporter ABCC2, dysfunction of which would lead to Dubin-Johnson syndrome. Here we determine the structures of ABCC2 in the apo, substrate-bound and ATP/ADP-bound forms using the cryo-electron microscopy, exhibiting a full transporter with a regulatory (R) domain inserted between the two half modules. Combined with substrate-stimulated ATPase and transport activity assays, structural analysis enables us to figure out transport cycle of ABCC2 with the R domain adopting various conformations. At the rest state, the R domain binding to the translocation cavity functions as an affinity filter that allows the substrates of high affinity to be transported in priority. Upon substrate binding, the R domain is expelled from the cavity and docks to the lateral of transmembrane domain following ATP hydrolysis. Our findings provide structural insights into a transport mechanism of ABC transporters finely tuned by the R domain.
History
DepositionJun 30, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 3, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Database references / Category: citation / citation_author
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.year

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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


Theoretical massNumber of molelcules
Total (without water)176,9651
Polymers176,9651
Non-polymers00
Water0
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: 176964.969 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 / Cell line (production host): HEK293F / 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

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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: ATP-binding cassette sub-family C member 2 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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 FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.18.2_3874: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 170268 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00411451
ELECTRON MICROSCOPYf_angle_d0.68215529
ELECTRON MICROSCOPYf_dihedral_angle_d25.7121508
ELECTRON MICROSCOPYf_chiral_restr0.0451820
ELECTRON MICROSCOPYf_plane_restr0.0051929

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