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- EMDB-24209: Structure of nevanimibe bound human ACAT2 -

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Basic information

Entry
Database: EMDB / ID: EMD-24209
TitleStructure of nevanimibe bound human ACAT2
Map dataStructure of nevanimibe bound human ACAT2
Sample
  • Organelle or cellular component: human ACAT2 with nevanimibe
    • Protein or peptide: Sterol O-acyltransferase 2
  • Ligand: nevanimibe
  • Ligand: CHOLESTEROL
  • Ligand: OLEIC ACID
KeywordsInhibitor / TRANSFERASE-Inhibitor complex
Function / homology
Function and homology information


sterol O-acyltransferase / sterol O-acyltransferase activity / cholesterol O-acyltransferase activity / macrophage derived foam cell differentiation / cholesterol storage / very-low-density lipoprotein particle assembly / fatty-acyl-CoA binding / low-density lipoprotein particle clearance / intestinal cholesterol absorption / LDL clearance ...sterol O-acyltransferase / sterol O-acyltransferase activity / cholesterol O-acyltransferase activity / macrophage derived foam cell differentiation / cholesterol storage / very-low-density lipoprotein particle assembly / fatty-acyl-CoA binding / low-density lipoprotein particle clearance / intestinal cholesterol absorption / LDL clearance / cholesterol efflux / acyltransferase activity / cholesterol binding / brush border / cholesterol metabolic process / cholesterol homeostasis / endoplasmic reticulum membrane / endoplasmic reticulum
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 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.93 Å
AuthorsLi X / Long T
CitationJournal: Structure / Year: 2021
Title: Molecular structures of human ACAT2 disclose mechanism for selective inhibition.
Authors: Tao Long / Yang Liu / Xiaochun Li /
Abstract: Endoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored ...Endoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored in cytosolic lipid droplets. Selective inhibition of ACAT2 has been shown to considerably attenuate hypercholesterolemia and atherosclerosis in mice. Here, we report cryogenic electron microscopy structures of human ACAT2 bound to its specific inhibitor pyripyropene A or the general ACAT inhibitor nevanimibe. Structural analysis reveals that ACAT2 has a topology in membranes similar to that of ACAT1. A catalytic core with an entry site occupied by a cholesterol molecule and another site for allosteric activation of ACAT2 is observed in these structures. Enzymatic assays show that mutations within sites of cholesterol entry or allosteric activation attenuate ACAT2 activity in vitro. Together, these results reveal mechanisms for ACAT2-mediated esterification of cholesterol, providing a blueprint to design new ACAT2 inhibitors for use in the prevention of cardiovascular disease.
History
DepositionJun 8, 2021-
Header (metadata) releaseSep 15, 2021-
Map releaseSep 15, 2021-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 6
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 6
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7n6r
  • Surface level: 6
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24209.png

Downloads & links

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Map

FileDownload / File: emd_24209.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of nevanimibe bound human ACAT2
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.83 Å/pix.
x 330 pix.
= 274.89 Å		0.83 Å/pix.
x 330 pix.
= 274.89 Å		0.83 Å/pix.
x 330 pix.
= 274.89 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.833 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 6.0 / Movie #1: 6
Minimum - Maximum-27.171768 - 40.061194999999998
Average (Standard dev.)0.00465659 (±1.0150539)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
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
start NX/NY/NZ000
NX/NY/NZ330330330
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS330330330
D min/max/mean-27.17240.0610.005

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Supplemental data

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Sample components

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Entire : human ACAT2 with nevanimibe

EntireName: human ACAT2 with nevanimibe
Components
  • Organelle or cellular component: human ACAT2 with nevanimibe
    • Protein or peptide: Sterol O-acyltransferase 2
  • Ligand: nevanimibe
  • Ligand: CHOLESTEROL
  • Ligand: OLEIC ACID

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Supramolecule #1: human ACAT2 with nevanimibe

SupramoleculeName: human ACAT2 with nevanimibe / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sterol O-acyltransferase 2

MacromoleculeName: Sterol O-acyltransferase 2 / 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: 60.893 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKE PGGARLRLQR TGGLGGERER QPCGDGNTET HRAPDLVQWT RHMEAVKAQL LEQAQGQLRE LLDRAMREAI QSYPSQDKP LPPPPPGSLS RTQEPSLGKQ KVFIIRKSLL DELMEVQHFR TIYHMFIAGL CVFIISTLAI DFIDEGRLLL E FDLLIFSF ...String:
MDYKDDDDKE PGGARLRLQR TGGLGGERER QPCGDGNTET HRAPDLVQWT RHMEAVKAQL LEQAQGQLRE LLDRAMREAI QSYPSQDKP LPPPPPGSLS RTQEPSLGKQ KVFIIRKSLL DELMEVQHFR TIYHMFIAGL CVFIISTLAI DFIDEGRLLL E FDLLIFSF GQLPLALVTW VPMFLSTLLA PYQALRLWAR GTWTQATGLG CALLAAHAVV LCALPVHVAV EHQLPPASRC VL VFEQVRF LMKSYSFLRE AVPGILRARR GEGIQAPSFS SYLYFLFCPT LIYRETYPRT PYVRWNYVAK NFAQALGCVL YAC FILGRL CVPVFANMSR EPFSTRALVL SILHATLPGI FMLLLIFFAF LHCWLNAFAE MLRFGDRMFY RDWWNSTSFS NYYR TWNVV VHDWLYSYVY QDGLRLLGAR ARGVAMLGVF LVSAVAHEYI FCFVLGFFYP VMLILFLVIG GMLNFMMHDQ RTGPA WNVL MWTMLFLGQG IQVSLYCQEW YARRHCPLPQ ATFWGLVTPR SWSCHT

UniProtKB: Sterol O-acyltransferase 2

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Macromolecule #2: nevanimibe

MacromoleculeName: nevanimibe / type: ligand / ID: 2 / Number of copies: 4 / Formula: ROV
Molecular weightTheoretical: 421.618 Da
Chemical component information

ChemComp-ROV:
nevanimibe

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 8 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #4: OLEIC ACID

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

ChemComp-OLA:
OLEIC ACID

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.93 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 210603
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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