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- PDB-7r8e: The structure of human ABCG1 E242Q complexed with ATP -

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Basic information

Entry
Database: PDB / ID: 7r8e
TitleThe structure of human ABCG1 E242Q complexed with ATP
ComponentsIsoform 4 of ATP-binding cassette sub-family G member 1
KeywordsLIPID TRANSPORT / sterol / lipids / ABC transporter
Function / homology
Function and homology information


ABC-type sterol transporter activity / glycoprotein transport / cellular response to high density lipoprotein particle stimulus / intracellular cholesterol transport / high-density lipoprotein particle remodeling / ABC transporters in lipid homeostasis / phospholipid efflux / toxin transmembrane transporter activity / floppase activity / cholesterol transfer activity ...ABC-type sterol transporter activity / glycoprotein transport / cellular response to high density lipoprotein particle stimulus / intracellular cholesterol transport / high-density lipoprotein particle remodeling / ABC transporters in lipid homeostasis / phospholipid efflux / toxin transmembrane transporter activity / floppase activity / cholesterol transfer activity / reverse cholesterol transport / positive regulation of cholesterol biosynthetic process / phospholipid homeostasis / phosphatidylcholine floppase activity / low-density lipoprotein particle remodeling / HDL remodeling / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / cholesterol efflux / regulation of cholesterol metabolic process / cholesterol binding / positive regulation of amyloid-beta formation / response to lipid / negative regulation of cholesterol storage / amyloid precursor protein catabolic process / positive regulation of cholesterol efflux / negative regulation of macrophage derived foam cell differentiation / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / cholesterol metabolic process / cholesterol homeostasis / response to organic substance / ADP binding / positive regulation of protein secretion / phospholipid binding / transmembrane transport / recycling endosome / endosome / protein heterodimerization activity / external side of plasma membrane / Golgi membrane / endoplasmic reticulum membrane / Golgi apparatus / ATP hydrolysis activity / protein homodimerization activity / mitochondrion / 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 / ATP-binding cassette, ABC transporter-type domain profile. ...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
ADENOSINE-5'-TRIPHOSPHATE / CHOLESTEROL / ATP-binding cassette sub-family G member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 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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Assembly

Deposited unit
A: Isoform 4 of ATP-binding cassette sub-family G member 1
B: Isoform 4 of ATP-binding cassette sub-family G member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,2928
Polymers148,4562
Non-polymers1,8366
Water0
1


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

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Components

#1: Protein Isoform 4 of ATP-binding cassette sub-family G member 1 / ATP-binding cassette transporter 8 / White protein homolog


Mass: 74228.000 Da / Num. of mol.: 2 / Mutation: E242Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCG1, ABC8, WHT1 / Production host: Homo sapiens (human)
References: UniProt: P45844, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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

ComponentName: ABCG1 transporter with cholesterol and ATP bound / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.15 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Added 8mM ATP, Magnesium and 0.2mg/ml cholesterol in ethanol
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: REFMAC / Version: 5.8.0258 / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1443662
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 72323 / Symmetry type: POINT
RefinementResolution: 3.68→213.25 Å / Cor.coef. Fo:Fc: 0.861 / SU B: 18.699 / SU ML: 0.266 / ESU R: 0.221 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.39376 --
obs0.39376 407373 100 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 121.852 Å2
Baniso -1Baniso -2Baniso -3
1-8.58 Å23.54 Å2-0.11 Å2
2---1.25 Å2-0.04 Å2
3----7.33 Å2
Refinement stepCycle: 1 / Total: 8702
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0030.0138887
ELECTRON MICROSCOPYr_bond_other_d0.0020.0178510
ELECTRON MICROSCOPYr_angle_refined_deg1.4041.65312040
ELECTRON MICROSCOPYr_angle_other_deg1.1271.58319646
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.89251090
ELECTRON MICROSCOPYr_dihedral_angle_2_deg28.12221.063414
ELECTRON MICROSCOPYr_dihedral_angle_3_deg16.506151530
ELECTRON MICROSCOPYr_dihedral_angle_4_deg16.2651558
ELECTRON MICROSCOPYr_chiral_restr0.0650.21156
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.029690
ELECTRON MICROSCOPYr_gen_planes_other0.0020.021942
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it0.95513.3094378
ELECTRON MICROSCOPYr_mcbond_other0.95513.3084377
ELECTRON MICROSCOPYr_mcangle_it1.72619.9625462
ELECTRON MICROSCOPYr_mcangle_other1.72519.9635463
ELECTRON MICROSCOPYr_scbond_it0.6713.2374509
ELECTRON MICROSCOPYr_scbond_other0.6713.2354510
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other1.24219.8146579
ELECTRON MICROSCOPYr_long_range_B_refined4.62710576
ELECTRON MICROSCOPYr_long_range_B_other4.62710577
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.681→3.776 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.856 29875 -
obs--100 %

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