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- EMDB-31547: Cryo-EM structure of the human cholesterol transporter ABCG1 in c... -

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Basic information

Entry
Database: EMDB / ID: EMD-31547
TitleCryo-EM structure of the human cholesterol transporter ABCG1 in complex with cholesterol
Map data
Sample
  • Complex: The complex of human ABCG1 with cholesterol and ATP
    • Protein or peptide: ATP-binding cassette sub-family G member 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: [(E,2S,3R)-2-(hexadecanoylamino)-3-oxidanyl-octadec-4-enyl] 2-(trimethylazaniumyl)ethyl phosphate
  • Ligand: CHOLESTEROL
Function / homology
Function and homology information


ABC-type sterol transporter activity / glycoprotein transport / cellular response to high density lipoprotein particle stimulus / intracellular cholesterol transport / ABC transporters in lipid homeostasis / toxin transmembrane transporter activity / floppase activity / positive regulation of cholesterol biosynthetic process / phospholipid homeostasis / phosphatidylcholine floppase activity ...ABC-type sterol transporter activity / glycoprotein transport / cellular response to high density lipoprotein particle stimulus / intracellular cholesterol transport / ABC transporters in lipid homeostasis / toxin transmembrane transporter activity / floppase activity / positive regulation of cholesterol biosynthetic process / phospholipid homeostasis / phosphatidylcholine floppase activity / high-density lipoprotein particle remodeling / phospholipid efflux / cholesterol transfer activity / reverse cholesterol transport / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / low-density lipoprotein particle remodeling / HDL remodeling / cholesterol efflux / cholesterol binding / regulation of cholesterol metabolic process / positive regulation of amyloid-beta formation / response to lipid / negative regulation of cholesterol storage / amyloid precursor protein catabolic process / negative regulation of macrophage derived foam cell differentiation / positive regulation of cholesterol efflux / 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
ATP-binding cassette sub-family G member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsXu D / Li YY / Yang FR / Sun CR / Pan JH / Wang L / Chen ZP / Fang SC / Yao XB / Hou WT ...Xu D / Li YY / Yang FR / Sun CR / Pan JH / Wang L / Chen ZP / Fang SC / Yao XB / Hou WT / Zhou CZ / Chen Y
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2020YFA0509302 China
CitationJournal: Cell Rep / Year: 2022
Title: Structure and transport mechanism of the human cholesterol transporter ABCG1.
Authors: Da Xu / Yanyan Li / Fengrui Yang / Cai-Rong Sun / Jinheng Pan / Liang Wang / Zhi-Peng Chen / Shu-Cheng Fang / Xuebiao Yao / Wen-Tao Hou / Cong-Zhao Zhou / Yuxing Chen /
Abstract: The reverse cholesterol transport pathway is responsible for the maintenance of human cholesterol homeostasis, an imbalance of which usually leads to atherosclerosis. As a key component of this ...The reverse cholesterol transport pathway is responsible for the maintenance of human cholesterol homeostasis, an imbalance of which usually leads to atherosclerosis. As a key component of this pathway, the ATP-binding cassette transporter ABCG1 forwards cellular cholesterol to the extracellular acceptor nascent high-density lipoprotein (HDL). Here, we report a 3.26-Å cryo-electron microscopy structure of cholesterol-bound ABCG1 in an inward-facing conformation, which represents a turnover condition upon ATP binding. Structural analyses combined with functional assays reveals that a cluster of conserved hydrophobic residues, in addition to two sphingomyelins, constitute a well-defined cholesterol-binding cavity. The exit of this cavity is closed by three pairs of conserved Phe residues, which constitute a hydrophobic path for the release of cholesterol in an acceptor concentration-dependent manner. Overall, we propose an ABCG1-driven cholesterol transport cycle initiated by sphingomyelin-assisted cholesterol recruitment and accomplished by the release of cholesterol to HDL.
History
DepositionJul 18, 2021-
Header (metadata) releaseJun 22, 2022-
Map releaseJun 22, 2022-
UpdateJun 29, 2022-
Current statusJun 29, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_31547.png

Downloads & links

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Map

FileDownload / File: emd_31547.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.01 Å
Density
Contour LevelBy AUTHOR: 0.46
Minimum - Maximum-1.229603 - 2.1042407
Average (Standard dev.)0.0043946165 (±0.05792929)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 242.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : The complex of human ABCG1 with cholesterol and ATP

EntireName: The complex of human ABCG1 with cholesterol and ATP
Components
  • Complex: The complex of human ABCG1 with cholesterol and ATP
    • Protein or peptide: ATP-binding cassette sub-family G member 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: [(E,2S,3R)-2-(hexadecanoylamino)-3-oxidanyl-octadec-4-enyl] 2-(trimethylazaniumyl)ethyl phosphate
  • Ligand: CHOLESTEROL

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Supramolecule #1: The complex of human ABCG1 with cholesterol and ATP

SupramoleculeName: The complex of human ABCG1 with cholesterol and ATP / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightTheoretical: 152 KDa

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

MacromoleculeName: 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: 75.670844 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 LWHRPSEEVK QTKRLKGLRK DSSSMEGCHS FSAS CLTQF CILFKRTFLS IMRDSVLTHL RITSHIGIGL LIGLLYLGIG NEAKKVLSNS GFLFFSMLFL MFAALMPTVL TFPLE MGVF LREHLNYWYS LKAYYLAKTM ADVPFQIMFP VAYCSIVYWM TSQPSDAVRF VLFAALGTMT SLVAQSLGLL IGAAST SLQ VATFVGPVTA IPVLLFSGFF VSFDTIPTYL QWMSYISYVR YGFEGVILSI YGLDREDLHC DIDETCHFQK SEAILRE LD VENAKLYLDF IVLGIFFISL RLIAYFVLRY KIRAER

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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 / Adenosine triphosphate

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Macromolecule #3: [(E,2S,3R)-2-(hexadecanoylamino)-3-oxidanyl-octadec-4-enyl] 2-(tr...

MacromoleculeName: [(E,2S,3R)-2-(hexadecanoylamino)-3-oxidanyl-octadec-4-enyl] 2-(trimethylazaniumyl)ethyl phosphate
type: ligand / ID: 3 / Number of copies: 2 / Formula: HWP
Molecular weightTheoretical: 703.028 Da
Chemical component information

ChemComp-HWP:
[(E,2S,3R)-2-(hexadecanoylamino)-3-oxidanyl-octadec-4-enyl] 2-(trimethylazaniumyl)ethyl phosphate

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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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

Concentration3.5 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 57.6 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 151593

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL / Overall B value: 142
Output model

PDB-7fdv:
Cryo-EM structure of the human cholesterol transporter ABCG1 in complex with cholesterol

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