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- EMDB-36709: Cryo-EM structure of bilirubin ditaurate (BDT) bound human ABC tr... -

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Basic information

Entry
Database: EMDB / ID: EMD-36709
TitleCryo-EM structure of bilirubin ditaurate (BDT) bound human ABC transporter ABCC2
Map data
Sample
  • Organelle or cellular component: ATP-binding cassette sub-family C member 2
    • Protein or peptide: ATP-binding cassette sub-family C member 2
  • Ligand: CHOLESTEROL
  • Ligand: 2-[3-[5-[(E)-(4-ethenyl-3-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-2-[[5-[(3-ethenyl-4-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-4-methyl-3-[3-oxidanylidene-3-(2-sulfoethylamino)propyl]-1H-pyrrol-2-yl]methyl]-4-methyl-1H-pyrrol-3-yl]propanoylamino]ethanesulfonic acid
KeywordsATP-dependent transporter / conjugated organic anions transporter / ATP hydrolyzes / TRANSPORT PROTEIN / 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 / Atorvastatin ADME / heme catabolic process ...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 / Atorvastatin ADME / heme catabolic process / organic anion transmembrane transporter activity / xenobiotic transmembrane transport / xenobiotic transport across blood-brain barrier / transepithelial transport / intercellular canaliculus / ABC-type xenobiotic transporter / Paracetamol ADME / ABC-type xenobiotic transporter activity / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / bile acid and bile salt transport / Heme degradation / Aspirin ADME / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / transport across blood-brain barrier / 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 ...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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.32 Å
AuthorsMao YX / Chen ZP / Wang L / Hou WT / Chen YX / Zhou CZ
Funding support China, 1 items
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
DepositionJul 1, 2023-
Header (metadata) releaseJan 3, 2024-
Map releaseJan 3, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36709.png

Downloads & links

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Map

FileDownload / File: emd_36709.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.229
Minimum - Maximum-0.33370262 - 1.1075033
Average (Standard dev.)0.0018050001 (±0.044908833)
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: #2

Fileemd_36709_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_36709_half_map_2.map
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Sample components

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Entire : ATP-binding cassette sub-family C member 2

EntireName: ATP-binding cassette sub-family C member 2
Components
  • Organelle or cellular component: ATP-binding cassette sub-family C member 2
    • Protein or peptide: ATP-binding cassette sub-family C member 2
  • Ligand: CHOLESTEROL
  • Ligand: 2-[3-[5-[(E)-(4-ethenyl-3-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-2-[[5-[(3-ethenyl-4-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-4-methyl-3-[3-oxidanylidene-3-(2-sulfoethylamino)propyl]-1H-pyrrol-2-yl]methyl]-4-methyl-1H-pyrrol-3-yl]propanoylamino]ethanesulfonic acid

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Supramolecule #1: ATP-binding cassette sub-family C member 2

SupramoleculeName: ATP-binding cassette sub-family C member 2 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: ATP-binding cassette sub-family C member 2

MacromoleculeName: ATP-binding cassette sub-family C member 2 / 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: 176.964969 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MLEKFCNSTF WNSSFLDSPE ADLPLCFEQT VLVWIPLGYL WLLAPWQLLH VYKSRTKRSS TTKLYLAKQV FVGFLLILAA IELALVLTE DSGQATVPAV RYTNPSLYLG TWLLVLLIQY SRQWCVQKNS WFLSLFWILS ILCGTFQFQT LIRTLLQGDN S NLAYSCLF ...String:
MLEKFCNSTF WNSSFLDSPE ADLPLCFEQT VLVWIPLGYL WLLAPWQLLH VYKSRTKRSS TTKLYLAKQV FVGFLLILAA IELALVLTE DSGQATVPAV RYTNPSLYLG TWLLVLLIQY SRQWCVQKNS WFLSLFWILS ILCGTFQFQT LIRTLLQGDN S NLAYSCLF FISYGFQILI LIFSAFSENN ESSNNPSSIA SFLSSITYSW YDSIILKGYK RPLTLEDVWE VDEEMKTKTL VS KFETHMK RELQKARRAL QRRQEKSSQQ NSGARLPGLN KNQSQSQDAL VLEDVEKKKK KSGTKKDVPK SWLMKALFKT FYM VLLKSF LLKLVNDIFT FVSPQLLKLL ISFASDRDTY LWIGYLCAIL LFTAALIQSF CLQCYFQLCF KLGVKVRTAI MASV YKKAL TLSNLARKEY TVGETVNLMS VDAQKLMDVT NFMHMLWSSV LQIVLSIFFL WRELGPSVLA GVGVMVLVIP INAIL STKS KTIQVKNMKN KDKRLKIMNE ILSGIKILKY FAWEPSFRDQ VQNLRKKELK NLLAFSQLQC VVIFVFQLTP VLVSVV TFS VYVLVDSNNI LDAQKAFTSI TLFNILRFPL SMLPMMISSM LQASVSTERL EKYLGGDDLD TSAIRHDCNF DKAMQFS EA SFTWEHDSEA TVRDVNLDIM AGQLVAVIGP VGSGKSSLIS AMLGEMENVH GHITIKGTTA YVPQQSWIQN GTIKDNIL F GTEFNEKRYQ QVLEACALLP DLEMLPGGDL AEIGEKGINL SGGQKQRISL ARATYQNLDI YLLDDPLSAV DAHVGKHIF NKVLGPNGLL KGKTRLLVTH SMHFLPQVDE IVVLGNGTIV EKGSYSALLA KKGEFAKNLK TFLRHTGPEE EATVHDGSEE EDDDYGLIS SVEEIPEDAA SITMRRENSF RRTLSRSSRS NGRHLKSLRN SLKTRNVNSL KEDEELVKGQ KLIKKEFIET G KVKFSIYL EYLQAIGLFS IFFIILAFVM NSVAFIGSNL WLSAWTSDSK IFNSTDYPAS QRDMRVGVYG ALGLAQGIFV FI AHFWSAF GFVHASNILH KQLLNNILRA PMRFFDTTPT GRIVNRFAGD ISTVDDTLPQ SLRSWITCFL GIISTLVMIC MAT PVFTII VIPLGIIYVS VQMFYVSTSR QLRRLDSVTR SPIYSHFSET VSGLPVIRAF EHQQRFLKHN EVRIDTNQKC VFSW ITSNR WLAIRLELVG NLTVFFSALM MVIYRDTLSG DTVGFVLSNA LNITQTLNWL VRMTSEIETN IVAVERITEY TKVEN EAPW VTDKRPPPDW PSKGKIQFNN YQVRYRPELD LVLRGITCDI GSMEKIGVVG RTGAGKSSLT NCLFRILEAA GGQIII DGV DIASIGLHDL REKLTIIPQD PILFSGSLRM NLDPFNNYSD EEIWKALELA HLKSFVASLQ LGLSHEVTEA GGNLSIG QR QLLCLGRALL RKSKILVLDE ATAAVDLETD NLIQTTIQNE FAHCTVITIA HRLHTIMDSD KVMVLDNGKI IECGSPEE L LQIPGPFYFM AKEAGIENVN STKFLEDYKD DDDKVEHHHH HHHH

UniProtKB: ATP-binding cassette sub-family C member 2

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Macromolecule #2: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 2 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #3: 2-[3-[5-[(E)-(4-ethenyl-3-methyl-5-oxidanylidene-pyrrol-2-ylidene...

MacromoleculeName: 2-[3-[5-[(E)-(4-ethenyl-3-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-2-[[5-[(3-ethenyl-4-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-4-methyl-3-[3-oxidanylidene-3-(2-sulfoethylamino) ...Name: 2-[3-[5-[(E)-(4-ethenyl-3-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-2-[[5-[(3-ethenyl-4-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-4-methyl-3-[3-oxidanylidene-3-(2-sulfoethylamino)propyl]-1H-pyrrol-2-yl]methyl]-4-methyl-1H-pyrrol-3-yl]propanoylamino]ethanesulfonic acid
type: ligand / ID: 3 / Number of copies: 1 / Formula: FEI
Molecular weightTheoretical: 798.925 Da
Chemical component information

ChemComp-FEI:
2-[3-[5-[(E)-(4-ethenyl-3-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-2-[[5-[(3-ethenyl-4-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-4-methyl-3-[3-oxidanylidene-3-(2-sulfoethylamino)propyl]-1H-pyrrol-2-yl]methyl]-4-methyl-1H-pyrrol-3-yl]propanoylamino]ethanesulfonic acid

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE / 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: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 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: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 368404
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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