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- PDB-7oz1: Cryo-EM structure of ABCG1 E242Q mutant with ATP and cholesteryl ... -

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Basic information

Entry
Database: PDB / ID: 7oz1
TitleCryo-EM structure of ABCG1 E242Q mutant with ATP and cholesteryl hemisuccinate bound
ComponentsIsoform 4 of ATP-binding cassette sub-family G member 1
KeywordsMEMBRANE PROTEIN / cholesterol / ABC transporter / ATP binding / inward-open
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 / : / cholesterol homeostasis / positive regulation of protein secretion / transmembrane transport / ADP binding / phospholipid binding / 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 / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / CHOLESTEROL HEMISUCCINATE / ATP-binding cassette sub-family G member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsSkarda, L. / Kowal, J. / Locher, K.P.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
CitationJournal: J Mol Biol / Year: 2021
Title: Structure of the Human Cholesterol Transporter ABCG1.
Authors: Liga Skarda / Julia Kowal / Kaspar P Locher /
Abstract: ABCG1 is an ATP binding cassette (ABC) transporter that removes excess cholesterol from peripheral tissues. Despite its role in preventing lipid accumulation and the development of cardiovascular and ...ABCG1 is an ATP binding cassette (ABC) transporter that removes excess cholesterol from peripheral tissues. Despite its role in preventing lipid accumulation and the development of cardiovascular and metabolic disease, the mechanism underpinning ABCG1-mediated cholesterol transport is unknown. Here we report a cryo-EM structure of human ABCG1 at 4 Å resolution in an inward-open state, featuring sterol-like density in the binding cavity. Structural comparison with the multidrug transporter ABCG2 and the sterol transporter ABCG5/G8 reveals the basis of mechanistic differences and distinct substrate specificity. Benzamil and taurocholate inhibited the ATPase activity of liposome-reconstituted ABCG1, whereas the ABCG2 inhibitor Ko143 did not. Based on the structural insights into ABCG1, we propose a mechanism for ABCG1-mediated cholesterol transport.
History
DepositionJun 25, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 22, 2021Provider: repository / Type: Initial release
Revision 2.0Sep 29, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / citation / em_admin / entity / pdbx_database_proc / pdbx_entity_nonpoly / pdbx_unobs_or_zero_occ_atoms
Item: _atom_site.Cartn_x / _atom_site.Cartn_y ..._atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site.pdbx_auth_atom_name / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.mon_nstd_flag / _chem_comp.name / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_unobs_or_zero_occ_atoms.auth_atom_id / _pdbx_unobs_or_zero_occ_atoms.label_atom_id

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Structure visualization

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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)157,71314
Polymers151,3172
Non-polymers6,39612
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area8950 Å2
ΔGint-66 kcal/mol
Surface area45930 Å2
MethodPISA

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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: 75658.508 Da / Num. of mol.: 2
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 / Comment: ATP, energy-carrying molecule*YM
#3: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C31H50O4
#4: Chemical ChemComp-PEE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE / Discrete optimized protein energy


Mass: 744.034 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C41H78NO8P / Comment: DOPE, phospholipid*YM
Has ligand of interestN

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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: Human ABCG1 with bound ATP and CHS / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaClSodium chloride1
225 mMHEPESC8H18N2O4S1
30.05 % (w/v)glycodiosgeninC56H92O251
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 1.76 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 17524

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.16_3549refinement
PHENIX1.16_3549refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 39791 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 41.31 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01829146
ELECTRON MICROSCOPYf_angle_d1.175812408
ELECTRON MICROSCOPYf_chiral_restr0.42181430
ELECTRON MICROSCOPYf_plane_restr0.00431490
ELECTRON MICROSCOPYf_dihedral_angle_d14.86195362

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