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- PDB-6vum: Structure of nevanimibe-bound human tetrameric ACAT1 -

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Basic information

Entry
Database: PDB / ID: 6vum
TitleStructure of nevanimibe-bound human tetrameric ACAT1
ComponentsSterol O-acyltransferase 1
KeywordsMEMBRANE PROTEIN / cholesterol / cholesteryl ester / acyltransferase / MBOAT
Function / homology
Function and homology information


sterol O-acyltransferase / sterol O-acyltransferase activity / cholesterol O-acyltransferase activity / cholesterol storage / positive regulation of amyloid precursor protein biosynthetic process / very-low-density lipoprotein particle assembly / low-density lipoprotein particle clearance / fatty-acyl-CoA binding / LDL clearance / cholesterol efflux ...sterol O-acyltransferase / sterol O-acyltransferase activity / cholesterol O-acyltransferase activity / cholesterol storage / positive regulation of amyloid precursor protein biosynthetic process / very-low-density lipoprotein particle assembly / low-density lipoprotein particle clearance / fatty-acyl-CoA binding / LDL clearance / cholesterol efflux / cholesterol binding / macrophage derived foam cell differentiation / cholesterol metabolic process / cholesterol homeostasis / endoplasmic reticulum membrane / endoplasmic reticulum / membrane / identical protein binding
Similarity search - Function
Sterol O-acyltransferase, metazoa / Sterol O-acyltransferase, ACAT/DAG/ARE types / Membrane bound O-acyl transferase, MBOAT / MBOAT, membrane-bound O-acyltransferase family
Similarity search - Domain/homology
Chem-3VV / CHOLESTEROL / COENZYME A / OLEIC ACID / nevanimibe / Sterol O-acyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.67 Å
AuthorsLi, X. / Long, T.
CitationJournal: Nature / Year: 2020
Title: Structure of nevanimibe-bound tetrameric human ACAT1.
Authors: Tao Long / Yingyuan Sun / Abdirahman Hassan / Xiaofeng Qi / Xiaochun Li /
Abstract: Cholesterol is an essential component of mammalian cell membranes, constituting up to 50% of plasma membrane lipids. By contrast, it accounts for only 5% of lipids in the endoplasmic reticulum (ER). ...Cholesterol is an essential component of mammalian cell membranes, constituting up to 50% of plasma membrane lipids. By contrast, it accounts for only 5% of lipids in the endoplasmic reticulum (ER). The ER enzyme sterol O-acyltransferase 1 (also named acyl-coenzyme A:cholesterol acyltransferase, ACAT1) transfers a long-chain fatty acid to cholesterol to form cholesteryl esters that coalesce into cytosolic lipid droplets. Under conditions of cholesterol overload, ACAT1 maintains the low cholesterol concentration of the ER and thereby has an essential role in cholesterol homeostasis. ACAT1 has also been implicated in Alzheimer's disease, atherosclerosis and cancers. Here we report a cryo-electron microscopy structure of human ACAT1 in complex with nevanimibe, an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The ACAT1 holoenzyme is a tetramer that consists of two homodimers. Each monomer contains nine transmembrane helices (TMs), six of which (TM4-TM9) form a cavity that accommodates nevanimibe and an endogenous acyl-coenzyme A. This cavity also contains a histidine that has previously been identified as essential for catalytic activity. Our structural data and biochemical analyses provide a physical model to explain the process of cholesterol esterification, as well as details of the interaction between nevanimibe and ACAT1, which may help to accelerate the development of ACAT1 inhibitors to treat related diseases.
History
DepositionFeb 16, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 13, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 3, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Sterol O-acyltransferase 1
B: Sterol O-acyltransferase 1
C: Sterol O-acyltransferase 1
D: Sterol O-acyltransferase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)273,48726
Polymers263,2054
Non-polymers10,28222
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Sterol O-acyltransferase 1 / / Acyl-coenzyme A:cholesterol acyltransferase 1 / ACAT-1 / Cholesterol acyltransferase 1


Mass: 65801.250 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOAT1, ACACT, ACACT1, ACAT, ACAT1, SOAT, STAT / Production host: Homo sapiens (human) / References: UniProt: P35610, sterol O-acyltransferase

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Non-polymers , 5 types, 22 molecules

#2: Chemical
ChemComp-OLA / OLEIC ACID / Oleic acid


Mass: 282.461 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H34O2
#3: Chemical
ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical
ChemComp-ROV / nevanimibe / N-({1-[4-(dimethylamino)phenyl]cyclopentyl}methyl)-N'-[2,6-di(propan-2-yl)phenyl]urea


Mass: 421.618 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H39N3O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-COA / COENZYME A / Coenzyme A


Mass: 767.534 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H36N7O16P3S
#6: Chemical ChemComp-3VV / S-{(3R,5R,9R)-1-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydrofuran-2-yl]-3,5,9-trihydroxy-8,8-dimethyl-3,5-dioxido-10,14-dioxo-2,4,6-trioxa-11,15-diaza-3lambda~5~,5lambda~5~-diphosphaheptadecan-17-yl} (9Z)-octadec-9-enethioate (non-preferred name) / oleoyl-CoA


Mass: 1031.980 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C39H68N7O17P3S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: ACAT1 / Type: CELL / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0135 / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.67 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 263839 / Symmetry type: POINT
RefinementResolution: 3.67→274.89 Å / Cor.coef. Fo:Fc: 0.801 / SU B: 22.557 / SU ML: 0.327 / ESU R: 0.213 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.4387 --
obs0.4387 880402 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: 111.677 Å2
Baniso -1Baniso -2Baniso -3
1-1.57 Å20.45 Å2-0.03 Å2
2--2.53 Å20 Å2
3----4.1 Å2
Refinement stepCycle: 1 / Total: 14388
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0080.0214946
ELECTRON MICROSCOPYr_bond_other_d0.0020.0214138
ELECTRON MICROSCOPYr_angle_refined_deg1.1871.9820426
ELECTRON MICROSCOPYr_angle_other_deg0.982332224
ELECTRON MICROSCOPYr_dihedral_angle_1_deg5.8551632
ELECTRON MICROSCOPYr_dihedral_angle_2_deg30.16221.288652
ELECTRON MICROSCOPYr_dihedral_angle_3_deg15.044152124
ELECTRON MICROSCOPYr_dihedral_angle_4_deg11.5991584
ELECTRON MICROSCOPYr_chiral_restr0.0660.22182
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.0216016
ELECTRON MICROSCOPYr_gen_planes_other0.0010.024048
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_it0.96311.6466540
ELECTRON MICROSCOPYr_mcbond_other0.96311.6466539
ELECTRON MICROSCOPYr_mcangle_it1.81117.4688168
ELECTRON MICROSCOPYr_mcangle_other1.81117.4688169
ELECTRON MICROSCOPYr_scbond_it0.54411.1568406
ELECTRON MICROSCOPYr_scbond_other0.54411.1568407
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other1.0816.74712259
ELECTRON MICROSCOPYr_long_range_B_refined5.02193.92817901
ELECTRON MICROSCOPYr_long_range_B_other5.02193.92917902
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.67→3.765 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rwork1.976 66025 -
Rfree-0 -
obs--100 %

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