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- PDB-6l47: Structure of the human sterol O-acyltransferase 1 in complex with... -

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Basic information

Entry
Database: PDB / ID: 6l47
TitleStructure of the human sterol O-acyltransferase 1 in complex with CI-976
ComponentsSterol O-acyltransferase 1
KeywordsMEMBRANE PROTEIN / TRANSFERASE / SOAT / ACAT / 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
CHOLESTEROL / Chem-E5L / Sterol O-acyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsChen, L. / Guan, C. / Niu, Y.
Funding support China, 5items
OrganizationGrant numberCountry
Ministry of Science and Technology (China)2016YFA0502004 China
National Natural Science Foundation of China31622021 China
National Science Foundation (China)91857000 China
National Science Foundation (China)31821091 China
National Natural Science Foundation of China31870833 China
CitationJournal: Nat Commun / Year: 2020
Title: Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor.
Authors: Chengcheng Guan / Yange Niu / Si-Cong Chen / Yunlu Kang / Jing-Xiang Wu / Koji Nishi / Catherine C Y Chang / Ta-Yuan Chang / Tuoping Luo / Lei Chen /
Abstract: Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the ...Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the esterification of cholesterol to generate cholesteryl esters for cholesterol storage. SOAT1 is a target to treat several human diseases. However, its structure and mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The structure of hSOAT1 dimer at 3.5 Å resolution reveals that a small molecule inhibitor CI-976 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, N421 and W420. Our results pave the way for future mechanistic study and rational drug design targeting hSOAT1 and other mammalian MBOAT family members.
History
DepositionOct 16, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 7, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)116,1506
Polymers114,5902
Non-polymers1,5604
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5520 Å2
ΔGint-37 kcal/mol
Surface area42710 Å2

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Components

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


Mass: 57294.777 Da / Num. of mol.: 2
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
#2: Chemical ChemComp-E5L / 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide


Mass: 393.560 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H39NO4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
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 sterol O-acyltransferase 1 dimer / Type: COMPLEX / 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: 50 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

EM softwareName: cisTEM / Category: 3D reconstruction
CTF correctionType: NONE
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 222018 / Details: cisTEM resolution limiting methods / Symmetry type: POINT

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