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- PDB-6vz1: Cryo-EM structure of human diacylglycerol O-acyltransferase 1 com... -

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Basic information

Entry
Database: PDB / ID: 6vz1
TitleCryo-EM structure of human diacylglycerol O-acyltransferase 1 complexed with acyl-CoA substrate
ComponentsDiacylglycerol O-acyltransferase 1Diglyceride acyltransferase
KeywordsTRANSFERASE / Triglyceride Biosynthesis / Lipid Storage / Lipid Metabolism
Function / homology
Function and homology information


retinol O-fatty-acyltransferase / 2-acylglycerol O-acyltransferase activity / retinol O-fatty-acyltransferase activity / monoacylglycerol biosynthetic process / Triglyceride biosynthesis / diacylglycerol metabolic process / Acyl chain remodeling of DAG and TAG / triglyceride biosynthetic process / long-chain fatty-acyl-CoA metabolic process / diacylglycerol O-acyltransferase ...retinol O-fatty-acyltransferase / 2-acylglycerol O-acyltransferase activity / retinol O-fatty-acyltransferase activity / monoacylglycerol biosynthetic process / Triglyceride biosynthesis / diacylglycerol metabolic process / Acyl chain remodeling of DAG and TAG / triglyceride biosynthetic process / long-chain fatty-acyl-CoA metabolic process / diacylglycerol O-acyltransferase / diacylglycerol O-acyltransferase activity / very-low-density lipoprotein particle assembly / lipid storage / triglyceride metabolic process / acyltransferase activity / fatty acid homeostasis / specific granule membrane / Neutrophil degranulation / endoplasmic reticulum membrane / membrane / identical protein binding / plasma membrane
Similarity search - Function
Diacylglycerol O-acyltransferase 1 / 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 / Chem-6OU / Diacylglycerol O-acyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsSui, X. / Wang, K. / Gluchowski, N. / Liao, M. / Walther, C.T. / Farese Jr., V.R.
Funding support United States, 4items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01GM124348 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5R01GM097194 United States
American Heart Association18POST34030308 United States
CitationJournal: Nature / Year: 2020
Title: Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme.
Authors: Xuewu Sui / Kun Wang / Nina L Gluchowski / Shane D Elliott / Maofu Liao / Tobias C Walther / Robert V Farese /
Abstract: Triacylglycerols store metabolic energy in organisms and have industrial uses as foods and fuels. Excessive accumulation of triacylglycerols in humans causes obesity and is associated with metabolic ...Triacylglycerols store metabolic energy in organisms and have industrial uses as foods and fuels. Excessive accumulation of triacylglycerols in humans causes obesity and is associated with metabolic diseases. Triacylglycerol synthesis is catalysed by acyl-CoA diacylglycerol acyltransferase (DGAT) enzymes, the structures and catalytic mechanisms of which remain unknown. Here we determined the structure of dimeric human DGAT1, a member of the membrane-bound O-acyltransferase (MBOAT) family, by cryo-electron microscopy at approximately 3.0 Å resolution. DGAT1 forms a homodimer through N-terminal segments and a hydrophobic interface, with putative active sites within the membrane region. A structure obtained with oleoyl-CoA substrate resolved at approximately 3.2 Å shows that the CoA moiety binds DGAT1 on the cytosolic side and the acyl group lies deep within a hydrophobic channel, positioning the acyl-CoA thioester bond near an invariant catalytic histidine residue. The reaction centre is located inside a large cavity, which opens laterally to the membrane bilayer, providing lipid access to the active site. A lipid-like density-possibly representing an acyl-acceptor molecule-is located within the reaction centre, orthogonal to acyl-CoA. Insights provided by the DGAT1 structures, together with mutagenesis and functional studies, provide the basis for a model of the catalysis of triacylglycerol synthesis by DGAT.
History
DepositionFeb 27, 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.name
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: Diacylglycerol O-acyltransferase 1
B: Diacylglycerol O-acyltransferase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,6148
Polymers110,6782
Non-polymers4,9366
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area8500 Å2
ΔGint-39 kcal/mol
Surface area43040 Å2

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Components

#1: Protein Diacylglycerol O-acyltransferase 1 / Diglyceride acyltransferase / ACAT-related gene product 1 / Acyl-CoA retinol O-fatty-acyltransferase / Retinol O-fatty- ...ACAT-related gene product 1 / Acyl-CoA retinol O-fatty-acyltransferase / Retinol O-fatty-acyltransferase / Diglyceride acyltransferase


Mass: 55339.133 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DGAT1, AGRP1, DGAT / Plasmid: pFasBacMam / Production host: Homo sapiens (human)
References: UniProt: O75907, diacylglycerol O-acyltransferase, retinol O-fatty-acyltransferase
#2: Chemical
ChemComp-6OU / [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate


Mass: 717.996 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C39H76NO8P / Comment: phospholipid*YM
#3: 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
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 diacylglycerol O-acyltransferase 1Diglyceride acyltransferase
Type: COMPLEX
Details: human diacylglycerol O-acyltransferase 1 complexed with oleoyl-CoA substrate
Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Plasmid: pFasBacMam
Buffer solutionpH: 7.5
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Protein sample was monodisperse.
VitrificationInstrument: GATAN CRYOPLUNGE 3 / Cryogen name: ETHANE / Humidity: 90 %

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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: 43 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 28165 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.017328
ELECTRON MICROSCOPYf_angle_d0.7919928
ELECTRON MICROSCOPYf_dihedral_angle_d11.8484334
ELECTRON MICROSCOPYf_chiral_restr0.051056
ELECTRON MICROSCOPYf_plane_restr0.0051224

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