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- EMDB-21390: Structure of nevanimibe-bound human tetrameric ACAT1 -

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Basic information

Entry
Database: EMDB / ID: EMD-21390
TitleStructure of nevanimibe-bound human tetrameric ACAT1
Map data
Sample
  • Cell: ACAT1
    • Protein or peptide: Sterol O-acyltransferase 1
  • Ligand: OLEIC ACID
  • Ligand: CHOLESTEROL
  • Ligand: nevanimibe
  • Ligand: COENZYME A
  • Ligand: 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)
Keywordscholesterol / cholesteryl ester / acyltransferase / MBOAT / MEMBRANE PROTEIN
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
Sterol O-acyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle 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, 2020-
Header (metadata) releaseMar 18, 2020-
Map releaseMay 13, 2020-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0094
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0094
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6vum
  • Surface level: 0.0094
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21390.png

Downloads & links

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Map

FileDownload / File: emd_21390.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.833 Å
Density
Contour LevelBy AUTHOR: 0.0094 / Movie #1: 0.0094
Minimum - Maximum-0.04810978 - 0.07537887
Average (Standard dev.)0.00015065777 (±0.002037241)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 274.89 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8330.8330.833
M x/y/z330330330
origin x/y/z0.0000.0000.000
length x/y/z274.890274.890274.890
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS330330330
D min/max/mean-0.0480.0750.000

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Supplemental data

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Sample components

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Entire : ACAT1

EntireName: ACAT1
Components
  • Cell: ACAT1
    • Protein or peptide: Sterol O-acyltransferase 1
  • Ligand: OLEIC ACID
  • Ligand: CHOLESTEROL
  • Ligand: nevanimibe
  • Ligand: COENZYME A
  • Ligand: 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)

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Supramolecule #1: ACAT1

SupramoleculeName: ACAT1 / type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sterol O-acyltransferase 1

MacromoleculeName: Sterol O-acyltransferase 1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: sterol O-acyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 65.80125 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVGEEKMSLR NRLSKSRENP EEDEDQRNPA KESLETPSNG RIDIKQLIAK KIKLTAEAEE LKPFFMKEVG SHFDDFVTNL IEKSASLDN GGCALTTFSV LEGEKNNHRA KDLRAPPEQG KIFIARRSLL DELLEVDHIR TIYHMFIALL ILFILSTLVV D YIDEGRLV ...String:
MVGEEKMSLR NRLSKSRENP EEDEDQRNPA KESLETPSNG RIDIKQLIAK KIKLTAEAEE LKPFFMKEVG SHFDDFVTNL IEKSASLDN GGCALTTFSV LEGEKNNHRA KDLRAPPEQG KIFIARRSLL DELLEVDHIR TIYHMFIALL ILFILSTLVV D YIDEGRLV LEFSLLSYAF GKFPTVVWTW WIMFLSTFSV PYFLFQHWAT GYSKSSHPLI RSLFHGFLFM IFQIGVLGFG PT YVVLAYT LPPASRFIII FEQIRFVMKA HSFVRENVPR VLNSAKEKSS TVPIPTVNQY LYFLFAPTLI YRDSYPRNPT VRW GYVAMK FAQVFGCFFY VYYIFERLCA PLFRNIKQEP FSARVLVLCV FNSILPGVLI LFLTFFAFLH CWLNAFAEML RFGD RMFYK DWWNSTSYSN YYRTWNVVVH DWLYYYAYKD FLWFFSKRFK SAAMLAVFAV SAVVHEYALA VCLSFFYPVL FVLFM FFGM AFNFIVNDSR KKPIWNVLMW TSLFLGNGVL LCFYSQEWYA RQHCPLKNPT FLDYVRPRSW TCRYVFDYKD DDDK

UniProtKB: Sterol O-acyltransferase 1

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Macromolecule #2: OLEIC ACID

MacromoleculeName: OLEIC ACID / type: ligand / ID: 2 / Number of copies: 4 / Formula: OLA
Molecular weightTheoretical: 282.461 Da
Chemical component information

ChemComp-OLA:
OLEIC ACID / Oleic acid

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 10 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #4: nevanimibe

MacromoleculeName: nevanimibe / type: ligand / ID: 4 / Number of copies: 4 / Formula: ROV
Molecular weightTheoretical: 421.618 Da
Chemical component information

ChemComp-ROV:
nevanimibe

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Macromolecule #5: COENZYME A

MacromoleculeName: COENZYME A / type: ligand / ID: 5 / Number of copies: 2 / Formula: COA
Molecular weightTheoretical: 767.534 Da
Chemical component information

ChemComp-COA:
COENZYME A / Coenzyme A

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Macromolecule #6: S-{(3R,5R,9R)-1-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydrox...

MacromoleculeName: 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- ...Name: 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)
type: ligand / ID: 6 / Number of copies: 2 / Formula: 3VV
Molecular weightTheoretical: 1.03198 KDa
Chemical component information

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)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.67 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 263839

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