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- PDB-7r88: The structure of human ABCG5-I529W/ABCG8-WT -

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Basic information

Entry
Database: PDB / ID: 7r88
TitleThe structure of human ABCG5-I529W/ABCG8-WT
Components
  • 2C7 Fab heavy chain
  • 2C7 Fab light chain
  • ATP-binding cassette sub-family G member 5
  • ATP-binding cassette sub-family G member 8
KeywordsLIPID TRANSPORT/IMMUNE SYSTEM / sterol / lipids / ABC transporter / LIPID TRANSPORT / LIPID TRANSPORT-IMMUNE SYSTEM complex
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsSun, Y. / Li, X. / Long, T.
Funding support United States, 3items
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 8, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: ATP-binding cassette sub-family G member 5
B: ATP-binding cassette sub-family G member 8
C: 2C7 Fab heavy chain
D: 2C7 Fab light chain


Theoretical massNumber of molelcules
Total (without water)206,8624
Polymers206,8624
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein ATP-binding cassette sub-family G member 5 / Sterolin-1


Mass: 74510.438 Da / Num. of mol.: 1 / Mutation: I529W
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCG5 / Production host: Homo sapiens (human)
References: UniProt: Q9H222, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
#2: Protein ATP-binding cassette sub-family G member 8 / Sterolin-2


Mass: 80365.828 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCG8 / Production host: Homo sapiens (human)
References: UniProt: Q9H221, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
#3: Antibody 2C7 Fab heavy chain


Mass: 26379.670 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
#4: Antibody 2C7 Fab light chain


Mass: 25605.615 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
Has ligand of interestN
Sequence detailsThe antibody was cleaved with papain to generate the Fab fragments. It is uncertain where papain ...The antibody was cleaved with papain to generate the Fab fragments. It is uncertain where papain cleaved, and not all of the Fab is visible in the map. The sequence provided for the heavy chain represents a possible sequence; however, the C-terminal end is uncertain.

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1ABCG5-I529W/ABCG8 transporter with Fab 2C7 boundCOMPLEXall0MULTIPLE SOURCES
2ABCG5-I529W/ABCG8 transporterCOMPLEX#1-#21RECOMBINANT
3Fab 2C7COMPLEX#3-#41RECOMBINANT
Molecular weightValue: 0.15 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Mus musculus (house mouse)10090
Buffer solutionpH: 7.5
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 293 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / C2 aperture diameter: 70 µm
Image recordingAverage exposure time: 1.8 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4900

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1400000
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 426781 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00211046
ELECTRON MICROSCOPYf_angle_d0.39314958
ELECTRON MICROSCOPYf_dihedral_angle_d10.7721505
ELECTRON MICROSCOPYf_chiral_restr0.0371704
ELECTRON MICROSCOPYf_plane_restr0.0031877

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