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- EMDB-20414: Structure of human ATP citrate lyase -

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Basic information

Entry
Database: EMDB / ID: EMD-20414
TitleStructure of human ATP citrate lyase
Map dataACLY-apo
Sample
  • Organelle or cellular component: ACLY apo
    • Protein or peptide: ATP-citrate synthase
Keywordsapo / LYASE
Function / homology
Function and homology information


ATP citrate synthase / ATP citrate synthase activity / citrate metabolic process / Fatty acyl-CoA biosynthesis / 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 / citrate metabolic process / Fatty acyl-CoA biosynthesis / 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
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-like, small alpha subdomain / Citrate synthase superfamily / Citrate synthase, C-terminal domain / Citrate synthase / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
ATP-citrate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsWei X / Marmorstein R
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P01 AG031862 United States
CitationJournal: 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
DepositionJul 3, 2019-
Header (metadata) releaseDec 25, 2019-
Map releaseJan 1, 2020-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
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  • Surface view colored by radius
  • Surface level: 0.02
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  • Surface view with fitted model
  • Atomic models: PDB-6pof
  • Surface level: 0.02
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20414.png

Downloads & links

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Map

FileDownload / File: emd_20414.map.gz / Format: CCP4 / Size: 10.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationACLY-apo
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.49 Å/pix.
x 140 pix.
= 207.9 Å		1.49 Å/pix.
x 140 pix.
= 207.9 Å		1.49 Å/pix.
x 140 pix.
= 207.9 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.485 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.123125315 - 0.18014595
Average (Standard dev.)0.001526998 (±0.007780556)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-70-70-70
Dimensions140140140
Spacing140140140
CellA=B=C: 207.90001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.4851.4851.485
M x/y/z140140140
origin x/y/z0.0000.0000.000
length x/y/z207.900207.900207.900
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ720720720
MAP C/R/S123
start NC/NR/NS-70-70-70
NC/NR/NS140140140
D min/max/mean-0.1230.1800.002

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Supplemental data

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Sample components

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Entire : ACLY apo

EntireName: ACLY apo
Components
  • Organelle or cellular component: ACLY apo
    • Protein or peptide: ATP-citrate synthase

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Supramolecule #1: ACLY apo

SupramoleculeName: ACLY apo / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 480 KDa

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Macromolecule #1: ATP-citrate synthase

MacromoleculeName: ATP-citrate synthase / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: ATP citrate synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 120.984141 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSAKAISEQT GKELLYKFIC TTSAIQNRFK YARVTPDTDW ARLLQDHPWL LSQNLVVKPD QLIKRRGKLG LVGVNLTLDG VKSWLKPRL GQEATVGKAT GFLKNFLIEP FVPHSQAEEF YVCIYATREG DYVLFHHEGG VDVGDVDAKA QKLLVGVDEK L NPEDIKKH ...String:
MSAKAISEQT GKELLYKFIC TTSAIQNRFK YARVTPDTDW ARLLQDHPWL LSQNLVVKPD QLIKRRGKLG LVGVNLTLDG VKSWLKPRL GQEATVGKAT GFLKNFLIEP FVPHSQAEEF YVCIYATREG DYVLFHHEGG VDVGDVDAKA QKLLVGVDEK L NPEDIKKH LLVHAPEDKK EILASFISGL FNFYEDLYFT YLEINPLVVT KDGVYVLDLA AKVDATADYI CKVKWGDIEF PP PFGREAY PEEAYIADLD AKSGASLKLT LLNPKGRIWT MVAGGGASVV YSDTICDLGG VNELANYGEY SGAPSEQQTY DYA KTILSL MTREKHPDGK ILIIGGSIAN FTNVAATFKG IVRAIRDYQG PLKEHEVTIF VRRGGPNYQE GLRVMGEVGK TTGI PIHVF GTETHMTAIV GMALGHRPIP NQPPTAAHTA NFLLNASGST STPAPSRTAS FSESRADEVA PAKKAKPAMP QDSVP SPRS LQGKSTTLFS RHTKAIVWGM QTRAVQGMLD FDYVCSRDEP SVAAMVYPFT GDHKQKFYWG HKEILIPVFK NMADAM RKH PEVDVLINFA SLRSAYDSTM ETMNYAQIRT IAIIAEGIPE ALTRKLIKKA DQKGVTIIGP ATVGGIKPGC FKIGNTG GM LDNILASKLY RPGSVAYVSR SGGMSNELNN IISRTTDGVY EGVAIGGDRY PGSTFMDHVL RYQDTPGVKM IVVLGEIG G TEEYKICRGI KEGRLTKPIV CWCIGTCATM FSSEVQFGHA GACANQASET AVAKNQALKE AGVFVPRSFD ELGEIIQSV YEDLVANGVI VPAQEVPPPT VPMDYSWARE LGLIRKPASF MTSICDERGQ ELIYAGMPIT EVFKEEMGIG GVLGLLWFQK RLPKYSCQF IEMCLMVTAD HGPAVSGAHN TIICARAGKD LVSSLTSGLL TIGDRFGGAL DAAAKMFSKA FDSGIIPMEF V NKMKKEGK LIMGIGHRVK SINNPDMRVQ ILKDYVRQHF PATPLLDYAL EVEKITTSKK PNLILNVDGL IGVAFVDMLR NC GSFTREE ADEYIDIGAL NGIFVLGRSM GFIGHYLDQK RLKQGLYRHP WDDISYVLPE HMSM

UniProtKB: ATP-citrate synthase

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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

Concentration1 mg/mL
BufferpH: 7.5 / Component - Concentration: 200.0 mM / Component - Formula: NaCl / Component - Name: sodium chloride
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 289 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.3 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: D2 (2x2 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 20677
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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