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- PDB-8etm: Human triacylglycerol synthesizing enzyme DGAT1 in complex with D... -

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Basic information

Entry
Database: PDB / ID: 8etm
TitleHuman triacylglycerol synthesizing enzyme DGAT1 in complex with DGAT1IN1 inhibitor
ComponentsDiacylglycerol O-acyltransferase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / triglyceride biosynthesis / lipid storage / lipid metabolism / membrane protein / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / long-chain fatty-acyl-CoA metabolic process / Acyl chain remodeling of DAG and TAG / triglyceride biosynthetic 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 / long-chain fatty-acyl-CoA metabolic process / Acyl chain remodeling of DAG and TAG / triglyceride biosynthetic 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 / identical protein binding / membrane / 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-WTT / Diacylglycerol O-acyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsSui, X. / Kun, W. / Walther, T. / Farese, R. / Liao, M.
Funding support United States, 2items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01GM124348 United States
CitationJournal: Nat Commun / Year: 2023
Title: Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis.
Authors: Xuewu Sui / Kun Wang / Kangkang Song / Chen Xu / Jiunn Song / Chia-Wei Lee / Maofu Liao / Robert V Farese / Tobias C Walther /
Abstract: Inhibitors of triacylglycerol (TG) synthesis have been developed to treat metabolism-related diseases, but we know little about their mechanisms of action. Here, we report cryo-EM structures of the ...Inhibitors of triacylglycerol (TG) synthesis have been developed to treat metabolism-related diseases, but we know little about their mechanisms of action. Here, we report cryo-EM structures of the TG-synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a membrane bound O-acyltransferase (MBOAT), in complex with two different inhibitors, T863 and DGAT1IN1. Each inhibitor binds DGAT1's fatty acyl-CoA substrate binding tunnel that opens to the cytoplasmic side of the ER. T863 blocks access to the tunnel entrance, whereas DGAT1IN1 extends further into the enzyme, with an amide group interacting with more deeply buried catalytic residues. A survey of DGAT1 inhibitors revealed that this amide group may serve as a common pharmacophore for inhibition of MBOATs. The inhibitors were minimally active against the related MBOAT acyl-CoA:cholesterol acyltransferase 1 (ACAT1), yet a single-residue mutation sensitized ACAT1 for inhibition. Collectively, our studies provide a structural foundation for developing DGAT1 and other MBOAT inhibitors.
History
DepositionOct 17, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 7, 2023Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: Mask / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: Mask / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jun 7, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.2Jun 4, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
Item: _em_admin.last_update / _em_software.name / _pdbx_entry_details.has_protein_modification
Revision 1.1Jun 4, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)111,7814
Polymers110,6782
Non-polymers1,1032
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Diacylglycerol O-acyltransferase 1 / 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 / Production host: Homo sapiens (human)
References: UniProt: O75907, diacylglycerol O-acyltransferase, retinol O-fatty-acyltransferase
#2: Chemical ChemComp-WTT / [(1S,4r)-4-{4-[(4S)-2-({[4-(trifluoromethoxy)phenyl]methyl}carbamoyl)imidazo[1,2-a]pyridin-6-yl]phenyl}cyclohexyl]acetic acid


Mass: 551.556 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H28F3N3O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: CryoEM density of human diacylglycerol O-acyltransferase 1 in complex with DGAT1IN1 inhibitor
Type: COMPLEX
Details: CryoEM density of human diacylglycerol O-acyltransferase 1 in complex with DGAT1IN1 inhibitor
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: FEI VITROBOT MARK IV / 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 FIELD / Nominal defocus max: 3500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14446 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0087022
ELECTRON MICROSCOPYf_angle_d0.7589562
ELECTRON MICROSCOPYf_dihedral_angle_d11.8724086
ELECTRON MICROSCOPYf_chiral_restr0.0441030
ELECTRON MICROSCOPYf_plane_restr0.0041224

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