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- EMDB-13118: Cryo-EM structure of ABCG1 E242Q mutant with ATP and cholesteryl ... -

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Basic information

Entry
Database: EMDB / ID: EMD-13118
TitleCryo-EM structure of ABCG1 E242Q mutant with ATP and cholesteryl hemisuccinate bound
Map data
Sample
  • Organelle or cellular component: Human ABCG1 with bound ATP and CHS
    • Protein or peptide: Isoform 4 of ATP-binding cassette sub-family G member 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
Function / homology
Function and homology information


ABC-type sterol transporter activity / cellular response to high density lipoprotein particle stimulus / intracellular cholesterol transport / glycoprotein transport / toxin transmembrane transporter activity / ABC transporters in lipid homeostasis / floppase activity / phospholipid efflux / phosphatidylcholine floppase activity / high-density lipoprotein particle remodeling ...ABC-type sterol transporter activity / cellular response to high density lipoprotein particle stimulus / intracellular cholesterol transport / glycoprotein transport / toxin transmembrane transporter activity / ABC transporters in lipid homeostasis / floppase activity / phospholipid efflux / phosphatidylcholine floppase activity / high-density lipoprotein particle remodeling / reverse cholesterol transport / phospholipid homeostasis / cholesterol transfer activity / xenobiotic detoxification by transmembrane export across the plasma membrane / low-density lipoprotein particle remodeling / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / HDL remodeling / cholesterol efflux / regulation of cholesterol metabolic process / cholesterol binding / positive regulation of amyloid-beta formation / response to lipid / amyloid precursor protein catabolic process / negative regulation of cholesterol storage / negative regulation of macrophage derived foam cell differentiation / positive regulation of cholesterol efflux / cholesterol metabolic process / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / cholesterol homeostasis / positive regulation of protein secretion / positive regulation of cholesterol biosynthetic process / recycling endosome / ADP binding / phospholipid binding / transmembrane transport / endosome / protein heterodimerization activity / Golgi membrane / external side of plasma membrane / intracellular membrane-bounded organelle / endoplasmic reticulum membrane / Golgi apparatus / protein homodimerization activity / ATP hydrolysis activity / mitochondrion / nucleoplasm / ATP binding / plasma membrane
Similarity search - Function
Pigment precursor permease/Protein ATP-binding cassette sub-family G / ABC transporter family G domain / ABC-2 type transporter / : / ABC-2 type transporter / ABC-2 type transporter / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain ...Pigment precursor permease/Protein ATP-binding cassette sub-family G / ABC transporter family G domain / ABC-2 type transporter / : / ABC-2 type transporter / ABC-2 type transporter / 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 G member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsSkarda L / Kowal J / Locher KP
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
CitationJournal: J Mol Biol / Year: 2021
Title: Structure of the Human Cholesterol Transporter ABCG1.
Authors: Liga Skarda / Julia Kowal / Kaspar P Locher /
Abstract: ABCG1 is an ATP binding cassette (ABC) transporter that removes excess cholesterol from peripheral tissues. Despite its role in preventing lipid accumulation and the development of cardiovascular and ...ABCG1 is an ATP binding cassette (ABC) transporter that removes excess cholesterol from peripheral tissues. Despite its role in preventing lipid accumulation and the development of cardiovascular and metabolic disease, the mechanism underpinning ABCG1-mediated cholesterol transport is unknown. Here we report a cryo-EM structure of human ABCG1 at 4 Å resolution in an inward-open state, featuring sterol-like density in the binding cavity. Structural comparison with the multidrug transporter ABCG2 and the sterol transporter ABCG5/G8 reveals the basis of mechanistic differences and distinct substrate specificity. Benzamil and taurocholate inhibited the ATPase activity of liposome-reconstituted ABCG1, whereas the ABCG2 inhibitor Ko143 did not. Based on the structural insights into ABCG1, we propose a mechanism for ABCG1-mediated cholesterol transport.
History
DepositionJun 25, 2021-
Header (metadata) releaseSep 22, 2021-
Map releaseSep 22, 2021-
UpdateSep 29, 2021-
Current statusSep 29, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7oz1
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_13118.png

Downloads & links

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Map

FileDownload / File: emd_13118.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 384 pix.
= 253.44 Å		0.66 Å/pix.
x 384 pix.
= 253.44 Å		0.66 Å/pix.
x 384 pix.
= 253.44 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.66 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.016 / Movie #1: 0.016
Minimum - Maximum-0.04864176 - 0.059445824
Average (Standard dev.)3.3738164e-05 (±0.0021319638)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 253.44 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.660.660.66
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z253.440253.440253.440
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-0.0490.0590.000

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Supplemental data

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Sample components

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Entire : Human ABCG1 with bound ATP and CHS

EntireName: Human ABCG1 with bound ATP and CHS
Components
  • Organelle or cellular component: Human ABCG1 with bound ATP and CHS
    • Protein or peptide: Isoform 4 of ATP-binding cassette sub-family G member 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

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Supramolecule #1: Human ABCG1 with bound ATP and CHS

SupramoleculeName: Human ABCG1 with bound ATP and CHS / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Isoform 4 of ATP-binding cassette sub-family G member 1

MacromoleculeName: Isoform 4 of ATP-binding cassette sub-family G member 1
type: protein_or_peptide / ID: 1 / Number of copies: 2 / 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: 75.658508 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MACLMAAFSV GTAMNASSYS AEMTEPKSVC VSVDEVVSSN MEATETDLLN GHLKKVDNNL TEAQRFSSLP RRAAVNIEFR DLSYSVPEG PWWRKKGYKT LLKGISGKFN SGELVAIMGP SGAGKSTLMN ILAGYRETGM KGAVLINGLP RDLRCFRKVS C YIMQDDML ...String:
MACLMAAFSV GTAMNASSYS AEMTEPKSVC VSVDEVVSSN MEATETDLLN GHLKKVDNNL TEAQRFSSLP RRAAVNIEFR DLSYSVPEG PWWRKKGYKT LLKGISGKFN SGELVAIMGP SGAGKSTLMN ILAGYRETGM KGAVLINGLP RDLRCFRKVS C YIMQDDML LPHLTVQEAM MVSAHLKLQE KDEGRREMVK EILTALGLLS CANTRTGSLS GGQRKRLAIA LELVNNPPVM FF DQPTSGL DSASCFQVVS LMKGLAQGGR SIICTIHQPS AKLFELFDQL YVLSQGQCVY RGKVCNLVPY LRDLGLNCPT YHN PADFVM EVASGEYGDQ NSRLVRAVRE GMCDSDHKRD LGGDAEVNPF LWHRPSEEDS SSMEGCHSFS ASCLTQFCIL FKRT FLSIM RDSVLTHLRI TSHIGIGLLI GLLYLGIGNE AKKVLSNSGF LFFSMLFLMF AALMPTVLTF PLEMGVFLRE HLNYW YSLK AYYLAKTMAD VPFQIMFPVA YCSIVYWMTS QPSDAVRFVL FAALGTMTSL VAQSLGLLIG AASTSLQVAT FVGPVT AIP VLLFSGFFVS FDTIPTYLQW MSYISYVRYG FEGVILSIYG LDREDLHCDI DETCHFQKSE AILRELDVEN AKLYLDF IV LGIFFISLRL IAYFVLRYKI RAERSSRVDT ETSQVAPA

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #3: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 8 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #4: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

MacromoleculeName: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / type: ligand / ID: 4 / Number of copies: 2 / Formula: PEE
Molecular weightTheoretical: 744.034 Da
Chemical component information

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM

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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

Concentration3 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
25.0 mMC8H18N2O4SHEPES
0.05 % (w/v)C56H92O25glycodiosgenin
GridModel: Quantifoil R1.2/1.3 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277.0 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 17524 / Average electron dose: 1.76 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 39791
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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