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Yorodumi- PDB-8etm: Human triacylglycerol synthesizing enzyme DGAT1 in complex with D... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8etm | |||||||||
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Title | Human triacylglycerol synthesizing enzyme DGAT1 in complex with DGAT1IN1 inhibitor | |||||||||
Components | Diacylglycerol O-acyltransferase 1 | |||||||||
Keywords | TRANSFERASE/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 / triglyceride biosynthetic process / Acyl chain remodeling of DAG and TAG / 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 / triglyceride biosynthetic process / Acyl chain remodeling of DAG and TAG / 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 / identical protein binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
Authors | Sui, X. / Kun, W. / Walther, T. / Farese, R. / Liao, M. | |||||||||
Funding support | United States, 2items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8etm.cif.gz | 157.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8etm.ent.gz | 124.4 KB | Display | PDB format |
PDBx/mmJSON format | 8etm.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8etm_validation.pdf.gz | 1.4 MB | Display | wwPDB validaton report |
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Full document | 8etm_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 8etm_validation.xml.gz | 35.4 KB | Display | |
Data in CIF | 8etm_validation.cif.gz | 50.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/et/8etm ftp://data.pdbj.org/pub/pdb/validation_reports/et/8etm | HTTPS FTP |
-Related structure data
Related structure data | 28594MC 8esmC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | 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 | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: 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 |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) / Plasmid: pFasBacMam |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Protein sample was monodisperse. |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 3500 nm / Nominal defocus min: 1500 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.16_3549: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14446 / Symmetry type: POINT | ||||||||||||||||||||||||
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