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- PDB-7fdv: Cryo-EM structure of the human cholesterol transporter ABCG1 in c... -

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Entry
Database: PDB / ID: 7fdv
TitleCryo-EM structure of the human cholesterol transporter ABCG1 in complex with cholesterol
ComponentsATP-binding cassette sub-family G member 1
KeywordsMEMBRANE PROTEIN / Human ABCG1 / cholsterol transporter / ATP-bound / 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 / phosphatidylcholine floppase activity / phospholipid homeostasis ...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 / phosphatidylcholine floppase activity / phospholipid homeostasis / 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 / response to organic substance / cholesterol homeostasis / positive regulation of protein secretion / ADP binding / phospholipid binding / transmembrane transport / recycling endosome / endosome / protein heterodimerization activity / external side of plasma membrane / Golgi membrane / endoplasmic reticulum membrane / Golgi apparatus / protein homodimerization activity / ATP hydrolysis 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 / Chem-HWP / ATP-binding cassette sub-family G member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsXu, D. / Li, Y.Y. / Yang, F.R. / Sun, C.R. / Pan, J.H. / Wang, L. / Chen, Z.P. / Fang, S.C. / Yao, X.B. / Hou, W.T. ...Xu, D. / Li, Y.Y. / Yang, F.R. / Sun, C.R. / Pan, J.H. / Wang, L. / Chen, Z.P. / Fang, S.C. / Yao, X.B. / Hou, W.T. / Zhou, C.Z. / Chen, Y.
Funding support China, 1items
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, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 22, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 29, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jun 12, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-binding cassette sub-family G member 1
D: ATP-binding cassette sub-family G member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)154,5358
Polymers151,3422
Non-polymers3,1946
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 75670.844 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCG1, ABC8, WHT1 / Cell line (production host): HEK 293F / 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-HWP / [(E,2S,3R)-2-(hexadecanoylamino)-3-oxidanyl-octadec-4-enyl] 2-(trimethylazaniumyl)ethyl phosphate / N-Palmitoylsphingomyelin


Mass: 703.028 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C39H79N2O6P / 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: The complex of human ABCG1 with cholesterol and ATP / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.152 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 3.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 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 / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 57.6 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 151593 / Symmetry type: POINT
Atomic model buildingB value: 142 / Protocol: AB INITIO MODEL

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