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- EMDB-28577: Human triacylglycerol synthesizing enzyme DGAT1 in complex with T... -

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Basic information

Entry
Database: EMDB / ID: EMD-28577
TitleHuman triacylglycerol synthesizing enzyme DGAT1 in complex with T863 inhibitor
Map data
Sample
  • Complex: CryoEM density of human diacylglycerol O-acyltransferase 1 in complex with T863 inhibitor
    • Protein or peptide: Diacylglycerol O-acyltransferase 1
  • Ligand: {(1r,4r)-4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}acetic acid
Keywordstriglyceride 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 / Acyl chain remodeling of DAG and TAG / long-chain fatty-acyl-CoA metabolic process / 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 / Acyl chain remodeling of DAG and TAG / long-chain fatty-acyl-CoA metabolic process / 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
Diacylglycerol O-acyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsSui X / Kun W / Walther T / Farese R / Liao M
Funding support United States, 2 items
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 14, 2022-
Header (metadata) releaseJun 7, 2023-
Map releaseJun 7, 2023-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28577.png

Downloads & links

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Map

FileDownload / File: emd_28577.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.87 Å
Density
Contour LevelBy AUTHOR: 0.0223
Minimum - Maximum-0.08215489 - 0.13517083
Average (Standard dev.)0.000026408525 (±0.0044728676)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 222.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_28577_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_28577_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_28577_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : CryoEM density of human diacylglycerol O-acyltransferase 1 in com...

EntireName: CryoEM density of human diacylglycerol O-acyltransferase 1 in complex with T863 inhibitor
Components
  • Complex: CryoEM density of human diacylglycerol O-acyltransferase 1 in complex with T863 inhibitor
    • Protein or peptide: Diacylglycerol O-acyltransferase 1
  • Ligand: {(1r,4r)-4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}acetic acid

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Supramolecule #1: CryoEM density of human diacylglycerol O-acyltransferase 1 in com...

SupramoleculeName: CryoEM density of human diacylglycerol O-acyltransferase 1 in complex with T863 inhibitor
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: CryoEM density of human diacylglycerol O-acyltransferase 1 in complex with T863 inhibitor
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Diacylglycerol O-acyltransferase 1

MacromoleculeName: Diacylglycerol O-acyltransferase 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: diacylglycerol O-acyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.339133 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGDRGSSRRR RTGSRPSSHG GGGPAAAEEE VRDAAAGPDV GAAGDAPAPA PNKDGDAGVG SGHWELRCHR LQDSLFSSDS GFSNYRGIL NWCVVMLILS NARLFLENLI KYGILVDPIQ VVSLFLKDPY SWPAPCLVIA ANVFAVAAFQ VEKRLAVGAL T EQAGLLLH ...String:
MGDRGSSRRR RTGSRPSSHG GGGPAAAEEE VRDAAAGPDV GAAGDAPAPA PNKDGDAGVG SGHWELRCHR LQDSLFSSDS GFSNYRGIL NWCVVMLILS NARLFLENLI KYGILVDPIQ VVSLFLKDPY SWPAPCLVIA ANVFAVAAFQ VEKRLAVGAL T EQAGLLLH VANLATILCF PAAVVLLVES ITPVGSLLAL MAHTILFLKL FSYRDVNSWC RRARAKAASA GKKASSAAAP HT VSYPDNL TYRDLYYFLF APTLCYELNF PRSPRIRKRF LLRRILEMLF FTQLQVGLIQ QWMVPTIQNS MKPFKDMDYS RII ERLLKL AVPNHLIWLI FFYWLFHSCL NAVAELMQFG DREFYRDWWN SESVTYFWQN WNIPVHKWCI RHFYKPMLRR GSSK WMART GVFLASAFFH EYLVSVPLRM FRLWAFTGMM AQIPLAWFVG RFFQGNYGNA AVWLSLIIGQ PIAVLMYVHD YYVLN YEAP AAEA

UniProtKB: Diacylglycerol O-acyltransferase 1

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Macromolecule #2: {(1r,4r)-4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin...

MacromoleculeName: {(1r,4r)-4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}acetic acid
type: ligand / ID: 2 / Number of copies: 2 / Formula: WS0
Molecular weightTheoretical: 394.467 Da
Chemical component information

ChemComp-WS0:
{(1r,4r)-4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]cyclohexyl}acetic acid

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration5 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Instrument: GATAN CRYOPLUNGE 3
DetailsProtein sample was monodisperse.

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Electron microscopy #1

Microscopy ID1
MicroscopeFEI TITAN KRIOS
Image recordingImage recording ID: 1 / Film or detector model: GATAN K3 (6k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 44.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Electron microscopy #1~

Microscopy ID1
MicroscopeFEI TALOS ARCTICA
Image recordingImage recording ID: 2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 37.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Image recording ID1
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 36885
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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