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- PDB-8hw4: Cryo-EM structure of dehydroepiandrosterone sulfate-bound human A... -

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Basic information

Entry
Database: PDB / ID: 8hw4
TitleCryo-EM structure of dehydroepiandrosterone sulfate-bound human ABC transporter ABCC3 in nanodiscs
ComponentsATP-binding cassette sub-family C member 3
KeywordsMEMBRANE PROTEIN / ABC transporter / TRANSPORT PROTEIN / multidrug resistance protein
Function / homology
Function and homology information


glucuronoside transmembrane transporter activity / icosanoid transmembrane transporter activity / ABC-type bile acid transporter activity / leukotriene transport / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / ATPase-coupled inorganic anion transmembrane transporter activity / xenobiotic transmembrane transport / ABC-type xenobiotic transporter / Paracetamol ADME ...glucuronoside transmembrane transporter activity / icosanoid transmembrane transporter activity / ABC-type bile acid transporter activity / leukotriene transport / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / ATPase-coupled inorganic anion transmembrane transporter activity / xenobiotic transmembrane transport / ABC-type xenobiotic transporter / Paracetamol ADME / xenobiotic transport / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / bile acid and bile salt transport / ABC-type xenobiotic transporter activity / NFE2L2 regulating MDR associated enzymes / Aspirin ADME / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / Recycling of bile acids and salts / xenobiotic metabolic process / basal plasma membrane / ABC-family proteins mediated transport / transmembrane transport / basolateral plasma membrane / ATP hydrolysis activity / ATP binding / membrane / 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
17-oxoandrost-5-en-3beta-yl hydrogen sulfate / ATP-binding cassette sub-family C member 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.52 Å
AuthorsWang, J. / Wang, F.F. / Chen, Y.X. / Zhou, C.Z.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: EMBO J / Year: 2023
Title: Placing steroid hormones within the human ABCC3 transporter reveals a compatible amphiphilic substrate-binding pocket.
Authors: Jie Wang / Xu Li / Fang-Fang Wang / Meng-Ting Cheng / Yao-Xu Mao / Shu-Cheng Fang / Liang Wang / Cong-Zhao Zhou / Wen-Tao Hou / Yuxing Chen /
Abstract: The human ABC transporter ABCC3 (also known as MRP3) transports a wide spectrum of substrates, including endogenous metabolites and exogenous drugs. Accordingly, it participates in multiple ...The human ABC transporter ABCC3 (also known as MRP3) transports a wide spectrum of substrates, including endogenous metabolites and exogenous drugs. Accordingly, it participates in multiple physiological processes and is involved in diverse human diseases such as intrahepatic cholestasis of pregnancy, which is caused by the intracellular accumulation of bile acids and estrogens. Here, we report three cryogenic electron microscopy structures of ABCC3: in the apo-form and in complexed forms bound to either the conjugated sex hormones β-estradiol 17-(β-D-glucuronide) and dehydroepiandrosterone sulfate. For both hormones, the steroid nuclei that superimpose against each other occupy the hydrophobic center of the transport cavity, whereas the two conjugation groups are separated and fixed by the hydrophilic patches in two transmembrane domains. Structural analysis combined with site-directed mutagenesis and ATPase activity assays revealed that ABCC3 possesses an amphiphilic substrate-binding pocket able to hold either conjugated hormone in an asymmetric pattern. These data build on consensus features of the substrate-binding pocket of MRPs and provide a structural platform for the rational design of inhibitors.
History
DepositionDec 28, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 7, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 2, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 30, 2023Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 1.3Sep 20, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.4Oct 11, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,2423
Polymers169,5051
Non-polymers7372
Water00
1


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

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Components

#1: Protein ATP-binding cassette sub-family C member 3 / Canalicular multispecific organic anion transporter 2 / Multi-specific organic anion transporter D ...Canalicular multispecific organic anion transporter 2 / Multi-specific organic anion transporter D / MOAT-D / Multidrug resistance-associated protein 3


Mass: 169504.719 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCC3, CMOAT2, MLP2, MRP3 / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
References: UniProt: O15438, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate, ABC-type xenobiotic transporter, ABC-type ...References: UniProt: O15438, 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-ZWY / 17-oxoandrost-5-en-3beta-yl hydrogen sulfate / Dehydroepiandrosterone sulfate / DHEA sulfate / DHEA-S


Mass: 368.488 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H28O5S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: Human dehydroepiandrosterone sulfate-bound ABC transporter ABCC3 in nanodiscs
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 169.4 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK 293F / Plasmid: pCAG
Buffer solutionpH: 8
SpecimenConc.: 1.85 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 54 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.52 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 240291 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00710945
ELECTRON MICROSCOPYf_angle_d0.78914886
ELECTRON MICROSCOPYf_dihedral_angle_d23.3591467
ELECTRON MICROSCOPYf_chiral_restr0.051737
ELECTRON MICROSCOPYf_plane_restr0.0051860

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