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- PDB-7n6r: Structure of nevanimibe bound human ACAT2 -

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Basic information

Entry
Database: PDB / ID: 7n6r
TitleStructure of nevanimibe bound human ACAT2
ComponentsSterol O-acyltransferase 2
KeywordsTRANSFERASE/Inhibitor / Inhibitor / 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
CHOLESTEROL / OLEIC ACID / nevanimibe / Sterol O-acyltransferase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single 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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 15, 2021Provider: repository / Type: Initial release
Revision 1.1May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

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Assembly

Deposited unit
A: Sterol O-acyltransferase 2
B: Sterol O-acyltransferase 2
C: Sterol O-acyltransferase 2
D: Sterol O-acyltransferase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)249,48220
Polymers243,5724
Non-polymers5,91016
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Sterol O-acyltransferase 2 / Acyl-coenzyme A:cholesterol acyltransferase 2 / ACAT-2 / Cholesterol acyltransferase 2


Mass: 60893.000 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOAT2, ACACT2, ACAT2 / Production host: Homo sapiens (human) / References: UniProt: O75908, sterol O-acyltransferase
#2: 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
#3: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical
ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H34O2
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: human ACAT2 with nevanimibe / Type: ORGANELLE OR CELLULAR COMPONENT / 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: DARK FIELD
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.93 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 210603 / Symmetry type: POINT

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