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- PDB-8erc: Human Membrane-bound O-acyltransferase 7 -

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Basic information

Entry
Database: PDB / ID: 8erc
TitleHuman Membrane-bound O-acyltransferase 7
ComponentsLysophospholipid acyltransferase 7
KeywordsMEMBRANE PROTEIN / lipid metabolism membrane remodeling
Function / homology
Function and homology information


2-acylglycerol-3-phosphate O-acyltransferase activity / 1-acylglycerol-3-phosphate O-acyltransferase activity / phosphatidylinositol acyl-chain remodeling / lysophospholipid acyltransferase activity / regulation of triglyceride metabolic process / lipid modification / phosphatidylcholine acyl-chain remodeling / O-acyltransferase activity / Acyl chain remodelling of PI / mitochondria-associated endoplasmic reticulum membrane contact site ...2-acylglycerol-3-phosphate O-acyltransferase activity / 1-acylglycerol-3-phosphate O-acyltransferase activity / phosphatidylinositol acyl-chain remodeling / lysophospholipid acyltransferase activity / regulation of triglyceride metabolic process / lipid modification / phosphatidylcholine acyl-chain remodeling / O-acyltransferase activity / Acyl chain remodelling of PI / mitochondria-associated endoplasmic reticulum membrane contact site / layer formation in cerebral cortex / ventricular system development / phosphatidylinositol biosynthetic process / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / endoplasmic reticulum membrane / endoplasmic reticulum / membrane
Similarity search - Function
Membrane bound O-acyl transferase, MBOAT / MBOAT, membrane-bound O-acyltransferase family
Similarity search - Domain/homology
Lysophospholipid acyltransferase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsWang, K. / Liao, M. / Farese, R.V. / Walther, T.C.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Research Resources (NIH/NCRR)R01GM141050 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Commun / Year: 2023
Title: The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification.
Authors: Kun Wang / Chia-Wei Lee / Xuewu Sui / Siyoung Kim / Shuhui Wang / Aidan B Higgs / Aaron J Baublis / Gregory A Voth / Maofu Liao / Tobias C Walther / Robert V Farese /
Abstract: Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound O-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with ...Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound O-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with arachidonyl-CoA. MBOAT7 mutations cause brain developmental disorders, and reduced expression is linked to fatty liver disease. In contrast, increased MBOAT7 expression is linked to hepatocellular and renal cancers. The mechanistic basis of MBOAT7 catalysis and substrate selectivity are unknown. Here, we report the structure and a model for the catalytic mechanism of human MBOAT7. Arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping them between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. Finally, the MBOAT7 structure and virtual screening enabled identification of small-molecule inhibitors that may serve as lead compounds for pharmacologic development.
History
DepositionOct 11, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Lysophospholipid acyltransferase 7


Theoretical massNumber of molelcules
Total (without water)54,1961
Polymers54,1961
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Lysophospholipid acyltransferase 7 / LPLAT 7 / 1-acylglycerophosphatidylinositol O-acyltransferase / Bladder and breast carcinoma- ...LPLAT 7 / 1-acylglycerophosphatidylinositol O-acyltransferase / Bladder and breast carcinoma-overexpressed gene 1 protein / Leukocyte receptor cluster member 4 / Lysophosphatidylinositol acyltransferase / LPIAT / Lyso-PI acyltransferase / Membrane-bound O-acyltransferase domain-containing protein 7 / O-acyltransferase domain-containing protein 7 / h-mboa-7


Mass: 54196.277 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MBOAT7, BB1, LENG4, OACT7 / Production host: Homo sapiens (human)
References: UniProt: Q96N66, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 2D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Membrane-bound O-acyltransferase 7 / Type: COMPLEX / Details: Purified protein / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 55 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 6 mg/ml / Embedding 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: OTHER / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 55.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 206418 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033634
ELECTRON MICROSCOPYf_angle_d0.644964
ELECTRON MICROSCOPYf_dihedral_angle_d3.449490
ELECTRON MICROSCOPYf_chiral_restr0.038537
ELECTRON MICROSCOPYf_plane_restr0.005612

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