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- EMDB-24310: The structure of human ABCG5-WT/ABCG8-I419E -

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Basic information

Entry
Database: EMDB / ID: EMD-24310
TitleThe structure of human ABCG5-WT/ABCG8-I419E
Map data
Sample
  • Complex: ABCG1 transporter with Fab 2C7
    • Complex: ABCG5/ABCG8 transporter
      • Protein or peptide: ATP-binding cassette sub-family G member 5
      • Protein or peptide: ATP-binding cassette sub-family G member 8
    • Complex: 2C7 Fab
      • Protein or peptide: 2C7 Fab heavy chain
      • Protein or peptide: 2C7 Fab light chain
Function / homology
Function and homology information


negative regulation of intestinal phytosterol absorption / negative regulation of intestinal cholesterol absorption / Defective ABCG8 causes GBD4 and sitosterolemia / Defective ABCG5 causes sitosterolemia / sterol transport / ABC transporters in lipid homeostasis / intestinal cholesterol absorption / cholesterol transfer activity / triglyceride homeostasis / phospholipid transport ...negative regulation of intestinal phytosterol absorption / negative regulation of intestinal cholesterol absorption / Defective ABCG8 causes GBD4 and sitosterolemia / Defective ABCG5 causes sitosterolemia / sterol transport / ABC transporters in lipid homeostasis / intestinal cholesterol absorption / cholesterol transfer activity / triglyceride homeostasis / phospholipid transport / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / cholesterol efflux / response to muscle activity / bile acid signaling pathway / response to ionizing radiation / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / ATP-binding cassette (ABC) transporter complex / response to nutrient / cholesterol homeostasis / transmembrane transport / receptor complex / response to xenobiotic stimulus / apical plasma membrane / protein heterodimerization activity / ATP hydrolysis activity / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
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 ...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 8 / ATP-binding cassette sub-family G member 5
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsSun Y / Li X / Long T
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
Welch Foundation United States
Damon Runyon Cancer Research Foundation United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2021
Title: Molecular basis of cholesterol efflux via ABCG subfamily transporters.
Authors: Yingyuan Sun / Jin Wang / Tao Long / Xiaofeng Qi / Linda Donnelly / Nadia Elghobashi-Meinhardt / Leticia Esparza / Jonathan C Cohen / Xiao-Song Xie / Helen H Hobbs / Xiaochun Li /
Abstract: The ABCG1 homodimer (G1) and ABCG5-ABCG8 heterodimer (G5G8), two members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter G family, are required for maintenance of cellular ...The ABCG1 homodimer (G1) and ABCG5-ABCG8 heterodimer (G5G8), two members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter G family, are required for maintenance of cellular cholesterol levels. G5G8 mediates secretion of neutral sterols into bile and the gut lumen, whereas G1 transports cholesterol from macrophages to high-density lipoproteins (HDLs). The mechanisms used by G5G8 and G1 to recognize and export sterols remain unclear. Here, we report cryoelectron microscopy (cryo-EM) structures of human G5G8 in sterol-bound and human G1 in cholesterol- and ATP-bound states. Both transporters have a sterol-binding site that is accessible from the cytosolic leaflet. A second site is present midway through the transmembrane domains of G5G8. The Walker A motif of G8 adopts a unique conformation that accounts for the marked asymmetry in ATPase activities between the two nucleotide-binding sites of G5G8. These structures, along with functional validation studies, provide a mechanistic framework for understanding cholesterol efflux via ABC transporters.
History
DepositionJun 26, 2021-
Header (metadata) releaseSep 8, 2021-
Map releaseSep 8, 2021-
UpdateSep 8, 2021-
Current statusSep 8, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7r87
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24310.png

Downloads & links

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Map

FileDownload / File: emd_24310.map.gz / Format: CCP4 / Size: 98.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.833 Å
Density
Contour LevelBy AUTHOR: 0.015 / Movie #1: 0.015
Minimum - Maximum-0.044245183 - 0.08177216
Average (Standard dev.)0.00022444813 (±0.0024125322)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions296296296
Spacing296296296
CellA=B=C: 246.56801 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8330.8330.833
M x/y/z296296296
origin x/y/z0.0000.0000.000
length x/y/z246.568246.568246.568
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ360360360
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS296296296
D min/max/mean-0.0440.0820.000

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Supplemental data

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Half map: #2

Fileemd_24310_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_24310_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : ABCG1 transporter with Fab 2C7

EntireName: ABCG1 transporter with Fab 2C7
Components
  • Complex: ABCG1 transporter with Fab 2C7
    • Complex: ABCG5/ABCG8 transporter
      • Protein or peptide: ATP-binding cassette sub-family G member 5
      • Protein or peptide: ATP-binding cassette sub-family G member 8
    • Complex: 2C7 Fab
      • Protein or peptide: 2C7 Fab heavy chain
      • Protein or peptide: 2C7 Fab light chain

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Supramolecule #1: ABCG1 transporter with Fab 2C7

SupramoleculeName: ABCG1 transporter with Fab 2C7 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 150 KDa

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Supramolecule #2: ABCG5/ABCG8 transporter

SupramoleculeName: ABCG5/ABCG8 transporter / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: 2C7 Fab

SupramoleculeName: 2C7 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Mus musculus (house mouse)

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Macromolecule #1: ATP-binding cassette sub-family G member 5

MacromoleculeName: ATP-binding cassette sub-family G member 5 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 74.437383 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGDLSSLTPG GSMGLQVNRG SQSSLEGAPA TAPEPHSLGI LHASYSVSHR VRPWWDITSC RQQWTRQILK DVSLYVESGQ IMCILGSSG SGKTTLLDAM SGRLGRAGTF LGEVYVNGRA LRREQFQDCF SYVLQSDTLL SSLTVRETLH YTALLAIRRG N PGSFQKKV ...String:
MGDLSSLTPG GSMGLQVNRG SQSSLEGAPA TAPEPHSLGI LHASYSVSHR VRPWWDITSC RQQWTRQILK DVSLYVESGQ IMCILGSSG SGKTTLLDAM SGRLGRAGTF LGEVYVNGRA LRREQFQDCF SYVLQSDTLL SSLTVRETLH YTALLAIRRG N PGSFQKKV EAVMAELSLS HVADRLIGNY SLGGISTGER RRVSIAAQLL QDPKVMLFDE PTTGLDCMTA NQIVVLLVEL AR RNRIVVL TIHQPRSELF QLFDKIAILS FGELIFCGTP AEMLDFFNDC GYPCPEHSNP FDFYMDLTSV DTQSKEREIE TSK RVQMIE SAYKKSAICH KTLKNIERMK HLKTLPMVPF KTKDSPGVFS KLGVLLRRVT RNLVRNKLAV ITRLLQNLIM GLFL LFFVL RVRSNVLKGA IQDRVGLLYQ FVGATPYTGM LNAVNLFPVL RAVSDQESQD GLYQKWQMML AYALHVLPFS VVATM IFSS VCYWTLGLHP EVARFGYFSA ALLAPHLIGE FLTLVLLGIV QNPNIVNSVV ALLSIAGVLV GSGFLRNIQE MPIPFK IIS YFTFQKYCSE ILVVNEFYGL NFTCGSSNVS VTTNPMCAFT QGIQFIEKTC PGATSRFTMN FLILYSFIPA LVILGIV VF KIRDHLISRG SHHHHHHGHH HHHH

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Macromolecule #2: ATP-binding cassette sub-family G member 8

MacromoleculeName: ATP-binding cassette sub-family G member 8 / type: protein_or_peptide / ID: 2 / 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: 80.381781 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAGKAAEERG LPKGATPQDT SGLQDRLFSS ESDNSLYFTY SGQPNTLEVR DLNYQVDLAS QVPWFEQLAQ FKMPWTSPSC QNSCELGIQ NLSFKVRSGQ MLAIIGSSGC GRASLLDVIT GRGHGGKIKS GQIWINGQPS SPQLVRKCVA HVRQHNQLLP N LTVRETLA ...String:
MAGKAAEERG LPKGATPQDT SGLQDRLFSS ESDNSLYFTY SGQPNTLEVR DLNYQVDLAS QVPWFEQLAQ FKMPWTSPSC QNSCELGIQ NLSFKVRSGQ MLAIIGSSGC GRASLLDVIT GRGHGGKIKS GQIWINGQPS SPQLVRKCVA HVRQHNQLLP N LTVRETLA FIAQMRLPRT FSQAQRDKRV EDVIAELRLR QCADTRVGNM YVRGLSGGER RRVSIGVQLL WNPGILILDE PT SGLDSFT AHNLVKTLSR LAKGNRLVLI SLHQPRSDIF RLFDLVLLMT SGTPIYLGAA QHMVQYFTAI GYPCPRYSNP ADF YVDLTS IDRRSREQEL ATREKAQSLA ALFLEKVRDL DDFLWKAETK DLDEDTCVES SVTPLDTNCL PSPTKMPGAV QQFT TLIRR QISNDFRDLP TLLEHGAEAC LMSMTIGFLY FGHGSIQLSF MDTAALLFMI GALIPFNVIL DVISKCYSER AMLYY ELED GLYTTGPYFF AKILGELPEH CAYIIIYGMP TYWLANLRPG LQPFLLHFLL VWLVVFCCRI MALAAAALLP TFHMAS FFS NALYNSFYLA GGFMINLSSL WTVPAWISKV SFLRWCFEGL MKIQFSRRTY KMPLGNLTIA VSGDKILSVM ELDSYPL YA IYLIVIGLSG GFMVLYYVSL RFIKQKPSQD WASNSLEVLF QGPNVDSKRR WKKNFIAVSA ANRFKKISSS GAL

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Macromolecule #3: 2C7 Fab heavy chain

MacromoleculeName: 2C7 Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.37967 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: MGWSCIILFL VATATGVHSE VKLVESGGGL VQPGGSLRLS CATSGFTFSE FFMEWVRQPP GKRLEWVAVS RNEANDYTTD YSASVKGRF IVSRDTSQNI LYLQMNALRA EDTAIYYCAR DAWMGFDYWG QGTTVTVSSA STKGPSVFPL APSSKSTSGG T AALGCLVK ...String:
MGWSCIILFL VATATGVHSE VKLVESGGGL VQPGGSLRLS CATSGFTFSE FFMEWVRQPP GKRLEWVAVS RNEANDYTTD YSASVKGRF IVSRDTSQNI LYLQMNALRA EDTAIYYCAR DAWMGFDYWG QGTTVTVSSA STKGPSVFPL APSSKSTSGG T AALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KS CDKTH

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Macromolecule #4: 2C7 Fab light chain

MacromoleculeName: 2C7 Fab light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 25.605615 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: MGWSCIILFL VATARTGVHS DIQMTQSPSS LSASLGERVS LTCRASQEIS GYLSWLQQKP DGTIQRLIYA AFSLDSGVPK RFSGSRSGS DYSLTISSLE SEDLAHYYCL QYASYPCTFG GGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF Y PREAKVQW ...String:
MGWSCIILFL VATARTGVHS DIQMTQSPSS LSASLGERVS LTCRASQEIS GYLSWLQQKP DGTIQRLIYA AFSLDSGVPK RFSGSRSGS DYSLTISSLE SEDLAHYYCL QYASYPCTFG GGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF Y PREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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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

Concentration10 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV
DetailsAdded 8mM ATP, Magnesium and 0.2mg/ml cholesterol in ethanol

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 4900 / Average exposure time: 1.8 sec. / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1443662
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 500000
FSC plot (resolution estimation)

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