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- PDB-7rig: Structure of ACLY-D1026A-substrates -

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Basic information

Entry
Database: PDB / ID: 7rig
TitleStructure of ACLY-D1026A-substrates
ComponentsATP-citrate synthase
KeywordsTRANSFERASE / mutant
Function / homology
Function and homology information


ATP citrate synthase / ATP citrate synthase activity / citrate metabolic process / Fatty acyl-CoA biosynthesis / acetyl-CoA biosynthetic process / ChREBP activates metabolic gene expression / coenzyme A metabolic process / oxaloacetate metabolic process / negative regulation of ferroptosis / cholesterol biosynthetic process ...ATP citrate synthase / ATP citrate synthase activity / citrate metabolic process / Fatty acyl-CoA biosynthesis / acetyl-CoA biosynthetic process / ChREBP activates metabolic gene expression / coenzyme A metabolic process / oxaloacetate metabolic process / negative regulation of ferroptosis / cholesterol biosynthetic process / lipid biosynthetic process / fatty acid biosynthetic process / azurophil granule lumen / ficolin-1-rich granule lumen / ciliary basal body / Neutrophil degranulation / extracellular exosome / extracellular region / nucleoplasm / ATP binding / metal ion binding / membrane / cytosol
Similarity search - Function
ATP-citrate synthase / : / ATP-citrate synthase ATP-grasp domain / ATP-citrate synthase, citrate-binding domain / ATP citrate lyase citrate-binding / Succinyl-CoA synthetase domains / 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. ...ATP-citrate synthase / : / ATP-citrate synthase ATP-grasp domain / ATP-citrate synthase, citrate-binding domain / ATP citrate lyase citrate-binding / Succinyl-CoA synthetase domains / 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 / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / COENZYME A / CITRATE ANION / PHOSPHATE ION / (3S)-citryl-Coenzyme A / Unknown ligand / ATP-citrate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.2 Å
AuthorsWei, X. / Marmorstein, R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Nat Commun / Year: 2023
Title: Allosteric role of the citrate synthase homology domain of ATP citrate lyase.
Authors: Xuepeng Wei / Kollin Schultz / Hannah L Pepper / Emily Megill / Austin Vogt / Nathaniel W Snyder / Ronen Marmorstein /
Abstract: ATP citrate lyase (ACLY) is the predominant nucleocytosolic source of acetyl-CoA and is aberrantly regulated in many diseases making it an attractive therapeutic target. Structural studies of ACLY ...ATP citrate lyase (ACLY) is the predominant nucleocytosolic source of acetyl-CoA and is aberrantly regulated in many diseases making it an attractive therapeutic target. Structural studies of ACLY reveal a central homotetrameric core citrate synthase homology (CSH) module flanked by acyl-CoA synthetase homology (ASH) domains, with ATP and citrate binding the ASH domain and CoA binding the ASH-CSH interface to produce acetyl-CoA and oxaloacetate products. The specific catalytic role of the CSH module and an essential D1026A residue contained within it has been a matter of debate. Here, we report biochemical and structural analysis of an ACLY-D1026A mutant demonstrating that this mutant traps a (3S)-citryl-CoA intermediate in the ASH domain in a configuration that is incompatible with the formation of acetyl-CoA, is able to convert acetyl-CoA and OAA to (3S)-citryl-CoA in the ASH domain, and can load CoA and unload acetyl-CoA in the CSH module. Together, this data support an allosteric role for the CSH module in ACLY catalysis.
History
DepositionJul 19, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2023Provider: repository / Type: Initial release
Revision 1.0May 10, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 10, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 10, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0May 10, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 10, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0May 10, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 10, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1May 31, 2023Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.2Jun 5, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.3May 28, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
Item: _em_admin.last_update / _em_software.name / _pdbx_entry_details.has_protein_modification
Revision 1.1May 28, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)493,82026
Polymers483,7614
Non-polymers10,06022
Water5,008278
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area45480 Å2
ΔGint-237 kcal/mol
Surface area149180 Å2

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 120940.125 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

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Non-polymers , 7 types, 300 molecules

#2: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical
ChemComp-Q5B / (3S)-citryl-Coenzyme A / (2~{S})-2-[2-[2-[3-[[(2~{R})-4-[[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxy-3,3-dimethyl-2-oxidanyl-butanoyl]amino]propanoylamino]ethylsulfanyl]-2-oxidanylidene-ethyl]-2-oxidanyl-butanedioic acid


Mass: 941.642 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H42N7O22P3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-FLC / CITRATE ANION


Mass: 189.100 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H5O7
#5: Chemical ChemComp-UNL / UNKNOWN LIGAND


Mass: 189.100 Da / Num. of mol.: 2 / Source method: obtained synthetically
#6: Chemical
ChemComp-COA / COENZYME A


Mass: 767.534 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C21H36N7O16P3S
#7: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 278 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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 D1026A mutant in complex with CoA and citrate / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.48 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenConc.: 4.5 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: BRIGHT FIELD
Image recordingElectron dose: 40 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
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1027706
3D reconstructionResolution: 2.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 378979 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00533232
ELECTRON MICROSCOPYf_angle_d0.67945084
ELECTRON MICROSCOPYf_dihedral_angle_d7.0914612
ELECTRON MICROSCOPYf_chiral_restr0.0484996
ELECTRON MICROSCOPYf_plane_restr0.0055712

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