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- EMDB-20904: Structure of human ATP citrate lyase in complex with acetyl-CoA a... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-20904 | |||||||||
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Title | Structure of human ATP citrate lyase in complex with acetyl-CoA and oxaloacetate | |||||||||
![]() | ATP citrate lyase in complex with acetyl-CoA and oxaloacetate | |||||||||
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Function / homology | ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() ![]() | |||||||||
![]() | Xuepeng W / Ronen M | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 16.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 13.6 KB 13.6 KB | Display Display | ![]() |
Images | ![]() | 211.1 KB | ||
Filedesc metadata | ![]() | 6.3 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6uv5MC ![]() 6poeC ![]() 6pofC ![]() 6ui9C ![]() 6uiaC ![]() 6uuwC ![]() 6uuzC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | ATP citrate lyase in complex with acetyl-CoA and oxaloacetate | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.87 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : ACLY in complex with acetyl-CoA and oxaloacetate
Entire | Name: ACLY in complex with acetyl-CoA and oxaloacetate![]() |
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Components |
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-Supramolecule #1: ACLY in complex with acetyl-CoA and oxaloacetate
Supramolecule | Name: ACLY in complex with acetyl-CoA and oxaloacetate / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 480 KDa |
-Macromolecule #1: ATP citrate lyase
Macromolecule | Name: ATP citrate lyase / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: ![]() |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 120.852938 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: 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 HMS UniProtKB: ATP-citrate synthase |
-Macromolecule #2: ACETYL COENZYME *A
Macromolecule | Name: ACETYL COENZYME *A / type: ligand / ID: 2 / Number of copies: 4 / Formula: ACO |
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Molecular weight | Theoretical: 809.571 Da |
Chemical component information | ![]() ChemComp-ACO: |
-Macromolecule #3: OXALOACETATE ION
Macromolecule | Name: OXALOACETATE ION / type: ligand / ID: 3 / Number of copies: 8 / Formula: OAA |
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Molecular weight | Theoretical: 131.064 Da |
Chemical component information | ![]() ChemComp-OAA: |
-Macromolecule #4: water
Macromolecule | Name: water / type: ligand / ID: 4 / Number of copies: 3 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Concentration | 4 mg/mL |
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Buffer | pH: 7.5 / Component - Concentration: 200.0 mM / Component - Formula: NaCl![]() ![]() |
Grid | Support film - Material: CARBON / Support film - topology: HOLEY / Details: unspecified |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 289 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Electron beam | Acceleration voltage: 200 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Sample stage | Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 3624 / Average exposure time: 1.3 sec. / Average electron dose: 40.0 e/Å2 |
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
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Image processing
Particle selection | Number selected: 719613 |
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Startup model | Type of model: OTHER |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: RELION |
Final angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: RELION |
Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3) / Number images used: 108738 |