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Yorodumi- PDB-6uia: Structure of ATP citrate lyase with CoA in a partially open confo... -
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-Basic information
Entry | Database: PDB / ID: 6uia | ||||||
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Title | Structure of ATP citrate lyase with CoA in a partially open conformation | ||||||
Components | ATP-citrate synthase | ||||||
Keywords | LYASE / open conformation | ||||||
Function / homology | Function and homology information ATP citrate synthase / ATP citrate synthase activity / Fatty acyl-CoA biosynthesis / citrate metabolic process / ChREBP activates metabolic gene expression / acetyl-CoA biosynthetic process / coenzyme A metabolic process / oxaloacetate metabolic process / lipid biosynthetic process / cholesterol biosynthetic process ...ATP citrate synthase / ATP citrate synthase activity / Fatty acyl-CoA biosynthesis / citrate metabolic process / ChREBP activates metabolic gene expression / acetyl-CoA biosynthetic process / coenzyme A metabolic process / oxaloacetate metabolic process / lipid biosynthetic process / cholesterol biosynthetic process / fatty acid biosynthetic process / azurophil granule lumen / ficolin-1-rich granule lumen / Neutrophil degranulation / extracellular exosome / extracellular region / nucleoplasm / ATP binding / membrane / metal ion binding / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å | ||||||
Authors | Wei, X. / Marmorstein, R. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Struct Mol Biol / Year: 2020 Title: Molecular basis for acetyl-CoA production by ATP-citrate lyase. Authors: Xuepeng Wei / Kollin Schultz / Gleb A Bazilevsky / Austin Vogt / Ronen Marmorstein / Abstract: ATP-citrate lyase (ACLY) synthesizes cytosolic acetyl coenzyme A (acetyl-CoA), a fundamental cellular building block. Accordingly, aberrant ACLY activity is observed in many diseases. Here we report ...ATP-citrate lyase (ACLY) synthesizes cytosolic acetyl coenzyme A (acetyl-CoA), a fundamental cellular building block. Accordingly, aberrant ACLY activity is observed in many diseases. Here we report cryo-EM structures of human ACLY, alone or bound to substrates or products. ACLY forms a homotetramer with a rigid citrate synthase homology (CSH) module, flanked by four flexible acetyl-CoA synthetase homology (ASH) domains; CoA is bound at the CSH-ASH interface in mutually exclusive productive or unproductive conformations. The structure of a catalytic mutant of ACLY in the presence of ATP, citrate and CoA substrates reveals a phospho-citryl-CoA intermediate in the ASH domain. ACLY with acetyl-CoA and oxaloacetate products shows the products bound in the ASH domain, with an additional oxaloacetate in the CSH domain, which could function in ACLY autoinhibition. These structures, which are supported by biochemical and biophysical data, challenge previous proposals of the ACLY catalytic mechanism and suggest additional therapeutic possibilities for ACLY-associated metabolic disorders. #1: Journal: Nat.Struct.Mol.Biol. / Year: 2019 Title: Molecular Basis for Acetyl-CoA Production by ATP-Citrate Lyase Authors: Wei, X. / Schultz, K. / Bazilevsky, G.A. / Vogt, A. / Marmorstein, R. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6uia.cif.gz | 751.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6uia.ent.gz | 609.3 KB | Display | PDB format |
PDBx/mmJSON format | 6uia.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6uia_validation.pdf.gz | 1 MB | Display | wwPDB validaton report |
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Full document | 6uia_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 6uia_validation.xml.gz | 116.2 KB | Display | |
Data in CIF | 6uia_validation.cif.gz | 174 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ui/6uia ftp://data.pdbj.org/pub/pdb/validation_reports/ui/6uia | HTTPS FTP |
-Related structure data
Related structure data | 20784MC 6poeC 6pofC 6ui9C 6uuwC 6uuzC 6uv5C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 120984.141 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ACLY / Production host: Escherichia coli (E. coli) / References: UniProt: P53396, ATP citrate synthase #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: ACLY in complex with CoA and citrate / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Value: 0.48 MDa / Experimental value: YES |
Source (natural) | Organism: Homo sapiens (human) / Cellular location: cytoplasm |
Source (recombinant) | Organism: Escherichia coli (E. coli) / Strain: BL21 / Plasmid: pet24a |
Buffer solution | pH: 7.5 |
Buffer component | Conc.: 200 mM / Name: Sodium Chloride / Formula: NaCl |
Specimen | Conc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: unspecified |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 289 K |
-Electron microscopy imaging
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |
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Microscopy | Model: FEI TALOS ARCTICA |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Cs: 2.7 mm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Average exposure time: 1.3 sec. / Electron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3624 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 716394 | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 73969 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Protocol: OTHER / Space: REAL | ||||||||||||||||||||||||
Atomic model building | PDB-ID: 3MWD Pdb chain-ID: A / Accession code: 3MWD / Source name: PDB / Type: experimental model |