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- PDB-7lj9: Structure of human ATP citrate lyase in complex with acetyl-CoA a... -

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Basic information

Entry
Database: PDB / ID: 7lj9
TitleStructure of human ATP citrate lyase in complex with acetyl-CoA and oxaloacetate
ComponentsATP-citrate synthase
KeywordsLYASE
Function / homology
Function and homology information


ATP citrate synthase activity / ATP citrate synthase / Fatty acyl-CoA biosynthesis / citrate metabolic process / ChREBP activates metabolic gene expression / acetyl-CoA biosynthetic process / oxaloacetate metabolic process / coenzyme A metabolic process / lipid biosynthetic process / cholesterol biosynthetic process ...ATP citrate synthase activity / ATP citrate synthase / Fatty acyl-CoA biosynthesis / citrate metabolic process / ChREBP activates metabolic gene expression / acetyl-CoA biosynthetic process / oxaloacetate metabolic process / coenzyme A metabolic process / lipid biosynthetic process / cholesterol biosynthetic process / tricarboxylic acid cycle / 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
ATP-citrate synthase / ATP-citrate synthase, citrate-binding domain / ATP citrate lyase citrate-binding / ATP-citrate lyase/succinyl-CoA ligase, active site / ATP-citrate lyase/succinyl-CoA ligase, conserved site / ATP-citrate lyase / succinyl-CoA ligases family active site. / ATP-citrate lyase / succinyl-CoA ligases family signature 1. / Succinyl-CoA synthetase, beta subunit, conserved site / ATP-citrate lyase / succinyl-CoA ligases family signature 3. / ATP-citrate lyase/succinyl-CoA ligase ...ATP-citrate synthase / ATP-citrate synthase, citrate-binding domain / ATP citrate lyase citrate-binding / ATP-citrate lyase/succinyl-CoA ligase, active site / ATP-citrate lyase/succinyl-CoA ligase, conserved site / ATP-citrate lyase / succinyl-CoA ligases family active site. / ATP-citrate lyase / succinyl-CoA ligases family signature 1. / Succinyl-CoA synthetase, beta subunit, conserved site / ATP-citrate lyase / succinyl-CoA ligases family signature 3. / ATP-citrate lyase/succinyl-CoA ligase / CoA-ligase / CoA binding domain / Succinyl-CoA synthetase-like / CoA binding domain / CoA-binding / Citrate synthase / Citrate synthase-like, small alpha subdomain / Citrate synthase superfamily / Citrate synthase, C-terminal domain / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
ACETYL COENZYME *A / OXALOACETATE ION / ATP-citrate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsWei, X. / Marmorstein, R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P01 AG031862 United States
Citation
Journal: Nat Struct Mol Biol / Year: 2021
Title: Reply to: Acetyl-CoA is produced by the citrate synthase homology module of ATP-citrate lyase.
Authors: Xuepeng Wei / Ronen Marmorstein /
#1: Journal: Nat Struct Mol Biol / Year: 2020
Title: Author Correction: Molecular basis for acetyl-CoA production by ATP-citrate lyase.
Authors: Xuepeng Wei / Kollin Schultz / Gleb A Bazilevsky / Austin Vogt / Ronen Marmorstein /
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
#2: 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.
History
DepositionJan 28, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 31, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 28, 2021Group: Database references / Category: citation / citation_author
Revision 1.2Aug 25, 2021Group: Database references / Category: citation / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3May 29, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / pdbx_initial_refinement_model
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type

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Structure visualization

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Assembly

Deposited unit
A: ATP-citrate synthase
B: ATP-citrate synthase
C: ATP-citrate synthase
D: ATP-citrate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)485,40110
Polymers483,9374
Non-polymers1,4656
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area31820 Å2
ΔGint-196 kcal/mol
Surface area68320 Å2

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Components

#1: Protein
ATP-citrate synthase / ATP-citrate (pro-S-)-lyase / ACL / Citrate cleavage enzyme


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
ChemComp-OAA / OXALOACETATE ION


Mass: 131.064 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H3O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ACO / ACETYL COENZYME *A


Mass: 809.571 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H38N7O17P3S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: ACLY in complex with acetyl-CoA and oxaloacetate / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.48 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human) / Strain: BL21(DE3) / Cellular location: cytoplasm
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: BL21 / Plasmid: pet24a
Buffer solutionpH: 7.5
Buffer componentConc.: 200 mM / Name: Sodium Chloride / Formula: NaCl
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 289 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingAverage 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

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM software
IDNameCategory
2SerialEMimage acquisition
4GctfCTF correction
7UCSF Chimeramodel fitting
9PHENIXmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 719613
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 205702 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Atomic model buildingPDB-ID: 3MWD

3mwd


Pdb chain-ID: A / Accession code: 3MWD / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01414825
ELECTRON MICROSCOPYf_angle_d1.31820046
ELECTRON MICROSCOPYf_dihedral_angle_d14.4622043
ELECTRON MICROSCOPYf_chiral_restr0.0762222
ELECTRON MICROSCOPYf_plane_restr0.012569

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