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- EMDB-35043: Cryo-EM structure of ABC transporter ABCC3 -

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Basic information

Entry
Database: EMDB / ID: EMD-35043
TitleCryo-EM structure of ABC transporter ABCC3
Map datahuman ABCC3
Sample
  • Complex: Human ABC transporter ABCC3 in nanodiscs
    • Protein or peptide: ATP-binding cassette sub-family C member 3
KeywordsABC transporter / TRANSPORT PROTEIN / multidrug resistance protein / MEMBRANE 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
ATP-binding cassette sub-family C member 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.07 Å
AuthorsWang J / Wang FF / Chen YX / Zhou CZ
Funding support China, 1 items
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 26, 2022-
Header (metadata) releaseJun 7, 2023-
Map releaseJun 7, 2023-
UpdateOct 11, 2023-
Current statusOct 11, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35043.png

Downloads & links

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Map

FileDownload / File: emd_35043.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationhuman ABCC3
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 0.717
Minimum - Maximum-1.5923538 - 3.137888
Average (Standard dev.)0.0014848801 (±0.08167431)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half A

Fileemd_35043_half_map_1.map
Annotationhalf_A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half B

Fileemd_35043_half_map_2.map
Annotationhalf_B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human ABC transporter ABCC3 in nanodiscs

EntireName: Human ABC transporter ABCC3 in nanodiscs
Components
  • Complex: Human ABC transporter ABCC3 in nanodiscs
    • Protein or peptide: ATP-binding cassette sub-family C member 3

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Supramolecule #1: Human ABC transporter ABCC3 in nanodiscs

SupramoleculeName: Human ABC transporter ABCC3 in nanodiscs / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 169.4 kDa/nm

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Macromolecule #1: ATP-binding cassette sub-family C member 3

MacromoleculeName: ATP-binding cassette sub-family C member 3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 169.504719 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDALCGSGEL GSKFWDSNLS VHTENPDLTP CFQNSLLAWV PCIYLWVALP CYLLYLRHHC RGYIILSHLS KLKMVLGVLL WCVSWADLF YSFHGLVHGR APAPVFFVTP LVVGVTMLLA TLLIQYERLQ GVQSSGVLII FWFLCVVCAI VPFRSKILLA K AEGEISDP ...String:
MDALCGSGEL GSKFWDSNLS VHTENPDLTP CFQNSLLAWV PCIYLWVALP CYLLYLRHHC RGYIILSHLS KLKMVLGVLL WCVSWADLF YSFHGLVHGR APAPVFFVTP LVVGVTMLLA TLLIQYERLQ GVQSSGVLII FWFLCVVCAI VPFRSKILLA K AEGEISDP FRFTTFYIHF ALVLSALILA CFREKPPFFS AKNVDPNPYP ETSAGFLSRL FFWWFTKMAI YGYRHPLEEK DL WSLKEED RSQMVVQQLL EAWRKQEKQT ARHKASAAPG KNASGEDEVL LGARPRPRKP SFLKALLATF GSSFLISACF KLI QDLLSF INPQLLSILI RFISNPMAPS WWGFLVAGLM FLCSMMQSLI LQHYYHYIFV TGVKFRTGIM GVIYRKALVI TNSV KRAST VGEIVNLMSV DAQRFMDLAP FLNLLWSAPL QIILAIYFLW QNLGPSVLAG VAFMVLLIPL NGAVAVKMRA FQVKQ MKLK DSRIKLMSEI LNGIKVLKLY AWEPSFLKQV EGIRQGELQL LRTAAYLHTT TTFTWMCSPF LVTLITLWVY VYVDPN NVL DAEKAFVSVS LFNILRLPLN MLPQLISNLT QASVSLKRIQ QFLSQEELDP QSVERKTISP GYAITIHSGT FTWAQDL PP TLHSLDIQVP KGALVAVVGP VGCGKSSLVS ALLGEMEKLE GKVHMKGSVA YVPQQAWIQN CTLQENVLFG KALNPKRY Q QTLEACALLA DLEMLPGGDQ TEIGEKGINL SGGQRQRVSL ARAVYSDADI FLLDDPLSAV DSHVAKHIFD HVIGPEGVL AGKTRVLVTH GISFLPQTDF IIVLADGQVS EMGPYPALLQ RNGSFANFLC NYAPDEDQGH LEDSWTALEG AEDKEALLIE DTLSNHTDL TDNDPVTYVV QKQFMRQLSA LSSDGEGQGR PVPRRHLGPS EKVQVTEAKA DGALTQEEKA AIGTVELSVF W DYAKAVGL CTTLAICLLY VGQSAAAIGA NVWLSAWTND AMADSRQNNT SLRLGVYAAL GILQGFLVML AAMAMAAGGI QA ARVLHQA LLHNKIRSPQ SFFDTTPSGR ILNCFSKDIY VVDEVLAPVI LMLLNSFFNA ISTLVVIMAS TPLFTVVILP LAV LYTLVQ RFYAATSRQL KRLESVSRSP IYSHFSETVT GASVIRAYNR SRDFEIISDT KVDANQRSCY PYIISNRWLS IGVE FVGNC VVLFAALFAV IGRSSLNPGL VGLSVSYSLQ VTFALNWMIR MMSDLESNIV AVERVKEYSK TETEAPWVVE GSRPP EGWP PRGEVEFRNY SVRYRPGLDL VLRDLSLHVH GGEKVGIVGR TGAGKSSMTL CLFRILEAAK GEIRIDGLNV ADIGLH DLR SQLTIIPQDP ILFSGTLRMN LDPFGSYSEE DIWWALELSH LHTFVSSQPA GLDFQCSEGG ENLSVGQRQL VCLARAL LR KSRILVLDEA TAAIDLETDN LIQATIRTQF DTCTVLTIAH RLNTIMDYTR VLVLDKGVVA EFDSPANLIA ARGIFYGM A RDAGLA

UniProtKB: ATP-binding cassette sub-family C member 3

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.4 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 51.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 587916
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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