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- EMDB-30791: Cryo-EM structure of the human ABCB6 (Hemin and GSH-bound) -

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Basic information

Entry
Database: EMDB / ID: EMD-30791
TitleCryo-EM structure of the human ABCB6 (Hemin and GSH-bound)
Map datagenerated from non-uniform refinement in CryoSparc
Sample
  • Complex: ABCB6
    • Protein or peptide: ATP-binding cassette sub-family B member 6, mitochondrial
  • Ligand: GLUTATHIONE
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE
Function / homology
Function and homology information


cellular detoxification of cadmium ion / Defective ABCB6 causes MCOPCB7 / heme transmembrane transport / Mitochondrial ABC transporters / tetrapyrrole metabolic process / ABC-type heme transporter / ABC-type heme transporter activity / porphyrin-containing compound metabolic process / tetrapyrrole binding / heme transport ...cellular detoxification of cadmium ion / Defective ABCB6 causes MCOPCB7 / heme transmembrane transport / Mitochondrial ABC transporters / tetrapyrrole metabolic process / ABC-type heme transporter / ABC-type heme transporter activity / porphyrin-containing compound metabolic process / tetrapyrrole binding / heme transport / heme metabolic process / porphyrin-containing compound biosynthetic process / melanosome assembly / melanosome membrane / multivesicular body membrane / mitochondrial envelope / endolysosome membrane / vacuolar membrane / skin development / efflux transmembrane transporter activity / intracellular copper ion homeostasis / ABC-type transporter activity / ATP-binding cassette (ABC) transporter complex / brain development / transmembrane transport / early endosome membrane / intracellular iron ion homeostasis / mitochondrial outer membrane / endosome / lysosomal membrane / Golgi membrane / heme binding / endoplasmic reticulum membrane / Golgi apparatus / endoplasmic reticulum / ATP hydrolysis activity / mitochondrion / extracellular exosome / nucleoplasm / ATP binding / plasma membrane / cytosol
Similarity search - Function
Mitochondrial ABC-transporter, N-terminal five TM domain / Mitochondrial ABC-transporter N-terminal five TM region / Type 1 protein exporter / 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 ...Mitochondrial ABC-transporter, N-terminal five TM domain / Mitochondrial ABC-transporter N-terminal five TM region / Type 1 protein exporter / 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 B member 6
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsKim S / Lee SS / Park JG / Kim JW / Kim NJ / Hong S / Kang JY / Jin MS
Funding support Korea, Republic Of, 4 items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)NRF-2017M3A9F6029753 Korea, Republic Of
National Research Foundation (NRF, Korea)NRF-2020R1I1A1A01072077 Korea, Republic Of
National Research Foundation (NRF, Korea)NRF-2019M3E5D6066058 Korea, Republic Of
National Research Foundation (NRF, Korea)NRF-2019R1A6A1A10073887 Korea, Republic Of
CitationJournal: Mol Cells / Year: 2022
Title: Structural Insights into Porphyrin Recognition by the Human ATP-Binding Cassette Transporter ABCB6.
Authors: Songwon Kim / Sang Soo Lee / Jun Gyou Park / Ji Won Kim / Seulgi Ju / Seung Hun Choi / Subin Kim / Na Jin Kim / Semi Hong / Jin Young Kang / Mi Sun Jin /
Abstract: Human ABCB6 is an ATP-binding cassette transporter that regulates heme biosynthesis by translocating various porphyrins from the cytoplasm into the mitochondria. Here we report the cryo-electron ...Human ABCB6 is an ATP-binding cassette transporter that regulates heme biosynthesis by translocating various porphyrins from the cytoplasm into the mitochondria. Here we report the cryo-electron microscopy (cryo-EM) structures of human ABCB6 with its substrates, coproporphyrin III (CPIII) and hemin, at 3.5 and 3.7 Å resolution, respectively. Metalfree porphyrin CPIII binds to ABCB6 within the central cavity, where its propionic acids form hydrogen bonds with the highly conserved Y550. The resulting structure has an overall fold similar to the inward-facing apo structure, but the two nucleotide-binding domains (NBDs) are slightly closer to each other. In contrast, when ABCB6 binds a metal-centered porphyrin hemin in complex with two glutathione molecules (1 hemin: 2 glutathione), the two NBDs end up much closer together, aligning them to bind and hydrolyze ATP more efficiently. In our structures, a glycine-rich and highly flexible "bulge" loop on TM helix 7 undergoes significant conformational changes associated with substrate binding. Our findings suggest that ABCB6 utilizes at least two distinct mechanisms to fine-tune substrate specificity and transport efficiency.
History
DepositionDec 11, 2020-
Header (metadata) releaseJun 22, 2022-
Map releaseJun 22, 2022-
UpdateAug 31, 2022-
Current statusAug 31, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_30791.png

Downloads & links

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Map

FileDownload / File: emd_30791.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationgenerated from non-uniform refinement in CryoSparc
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.306
Minimum - Maximum-0.8491686 - 1.2225008
Average (Standard dev.)0.0026336685 (±0.045921065)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 232.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : ABCB6

EntireName: ABCB6
Components
  • Complex: ABCB6
    • Protein or peptide: ATP-binding cassette sub-family B member 6, mitochondrial
  • Ligand: GLUTATHIONE
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE

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Supramolecule #1: ABCB6

SupramoleculeName: ABCB6 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper) / Recombinant cell: BTI-Tn-5B1-4

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Macromolecule #1: ATP-binding cassette sub-family B member 6, mitochondrial

MacromoleculeName: ATP-binding cassette sub-family B member 6, mitochondrial
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.974172 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MVTVGNYCEA EGPVGPAWMQ DGLSPCFFFT LVPSTRMALG TLALVLALPC RRRERPAGAD SLSWGAGPRI SPYVLQLLLA TLQAALPLA GLAGRVGTAR GAPLPSYLLL ASVLESLAGA CGLWLLVVER SQARQRLAMG IWIKFRHSPG LLLLWTVAFA A ENLALVSW ...String:
MVTVGNYCEA EGPVGPAWMQ DGLSPCFFFT LVPSTRMALG TLALVLALPC RRRERPAGAD SLSWGAGPRI SPYVLQLLLA TLQAALPLA GLAGRVGTAR GAPLPSYLLL ASVLESLAGA CGLWLLVVER SQARQRLAMG IWIKFRHSPG LLLLWTVAFA A ENLALVSW NSPQWWWARA DLGQQVQFSL WVLRYVVSGG LFVLGLWAPG LRPQSYTLQV HEEDQDVERS QVRSAAQQST WR DFGRKLR LLSGYLWPRG SPALQLVVLI CLGLMGLERA LNVLVPIFYR NIVNLLTEKA PWNSLAWTVT SYVFLKFLQG GGT GSTGFV SNLRTFLWIR VQQFTSRRVE LLIFSHLHEL SLRWHLGRRT GEVLRIADRG TSSVTGLLSY LVFNVIPTLA DIII GIIYF SMFFNAWFGL IVFLCMSLYL TLTIVVTEWR TKFRRAMNTQ ENATRARAVD SLLNFETVKY YNAESYEVER YREAI IKYQ GLEWKSSASL VLLNQTQNLV IGLGLLAGSL LCAYFVTEQK LQVGDYVLFG TYIIQLYMPL NWFGTYYRMI QTNFID MEN MFDLLKEETE VKDLPGAGPL RFQKGRIEFE NVHFSYADGR ETLQDVSFTV MPGQTLALVG PSGAGKSTIL RLLFRFY DI SSGCIRIDGQ DISQVTQASL RSHIGVVPQD TVLFNDTIAD NIRYGRVTAG NDEVEAAAQA AGIHDAIMAF PEGYRTQV G ERGLKLSGGE KQRVAIARTI LKAPGIILLD EATSALDTSN ERAIQASLAK VCANRTTIVV AHRLSTVVNA DQILVIKDG CIVERGRHEA LLSRGGVYAD MWQLQQGQEE TSEDTKPQTM ER

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Macromolecule #2: GLUTATHIONE

MacromoleculeName: GLUTATHIONE / type: ligand / ID: 2 / Number of copies: 4 / Formula: GSH
Molecular weightTheoretical: 307.323 Da
Chemical component information

ChemComp-GSH:
GLUTATHIONE / Glutathione

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Macromolecule #3: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 6 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #4: PROTOPORPHYRIN IX CONTAINING FE

MacromoleculeName: PROTOPORPHYRIN IX CONTAINING FE / type: ligand / ID: 4 / Number of copies: 1 / Formula: HEM
Molecular weightTheoretical: 616.487 Da
Chemical component information

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE / Heme B

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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

Concentration6 mg/mL
BufferpH: 7
Component:
ConcentrationFormulaName
200.0 mMNaClSodium chloridesodium chloride
0.056 %C24H44O11CYMAL-6
0.056 %C31H50O4C4H11NO3Cholesteryl Hemisuccinate Tris Salt
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample was monodisperse.

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4mrp


Details: We also used PDB ID 3NH6 as a startup model.
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.15.0)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 283866

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-7dnz:
Cryo-EM structure of the human ABCB6 (Hemin and GSH-bound)

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