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- EMDB-36704: Human 3-methylcrotonyl-CoA carboxylase in MCCU state with MCoA -

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Basic information

Entry
Database: EMDB / ID: EMD-36704
TitleHuman 3-methylcrotonyl-CoA carboxylase in MCCU state with MCoA
Map data
Sample
  • Complex: Dodecamer of human MCC
    • Protein or peptide: Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial
    • Protein or peptide: Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial
  • Ligand: ~{S}-[2-[3-[[(2~{R})-4-[[[(2~{S},3~{S},4~{S},5~{S})-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]ethyl] 3-methylbut-2-enethioate
  • Ligand: 5-(HEXAHYDRO-2-OXO-1H-THIENO[3,4-D]IMIDAZOL-6-YL)PENTANAL
KeywordsMCC / Mitochondrial / CYTOSOLIC PROTEIN
Function / homology
Function and homology information


3-Methylcrotonyl-CoA carboxylase deficiency / methylcrotonoyl-CoA carboxylase / biotin metabolic process / methylcrotonoyl-CoA carboxylase complex / methylcrotonoyl-CoA carboxylase activity / Defective HLCS causes multiple carboxylase deficiency / Biotin transport and metabolism / L-leucine catabolic process / biotin carboxylase activity / branched-chain amino acid catabolic process ...3-Methylcrotonyl-CoA carboxylase deficiency / methylcrotonoyl-CoA carboxylase / biotin metabolic process / methylcrotonoyl-CoA carboxylase complex / methylcrotonoyl-CoA carboxylase activity / Defective HLCS causes multiple carboxylase deficiency / Biotin transport and metabolism / L-leucine catabolic process / biotin carboxylase activity / branched-chain amino acid catabolic process / Branched-chain amino acid catabolism / coenzyme A metabolic process / biotin binding / mitochondrial matrix / mitochondrion / ATP binding / metal ion binding / cytosol
Similarity search - Function
Methylcrotonoyl-CoA carboxylase beta chain MCCB/AccD1-like / : / Acetyl-coenzyme A carboxyltransferase, C-terminal / Acetyl-coenzyme A (CoA) carboxyltransferase C-terminal domain profile. / Acetyl-coenzyme A carboxyltransferase, N-terminal / Acetyl-coenzyme A (CoA) carboxyltransferase N-terminal domain profile. / Acetyl-CoA carboxylase / Carboxyl transferase domain / Biotin-binding site / Biotin-requiring enzymes attachment site. ...Methylcrotonoyl-CoA carboxylase beta chain MCCB/AccD1-like / : / Acetyl-coenzyme A carboxyltransferase, C-terminal / Acetyl-coenzyme A (CoA) carboxyltransferase C-terminal domain profile. / Acetyl-coenzyme A carboxyltransferase, N-terminal / Acetyl-coenzyme A (CoA) carboxyltransferase N-terminal domain profile. / Acetyl-CoA carboxylase / Carboxyl transferase domain / Biotin-binding site / Biotin-requiring enzymes attachment site. / Biotin carboxylase-like, N-terminal domain / Biotin carboxylase, C-terminal / Biotin carboxylation domain / Biotin carboxylase, N-terminal domain / Biotin carboxylase C-terminal domain / Biotin carboxylation domain profile. / Biotin carboxylase C-terminal domain / Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain / Carbamoyl-phosphate synthase L chain, ATP binding domain / Biotin-requiring enzyme / Rudiment single hybrid motif / Biotinyl/lipoyl domain profile. / Biotin/lipoyl attachment / Single hybrid motif / Pre-ATP-grasp domain superfamily / ATP-grasp fold / ATP-grasp fold profile. / ClpP/crotonase-like domain superfamily / Carbamoyl-phosphate synthase subdomain signature 2.
Similarity search - Domain/homology
Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial / Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsLiu DS / Su JY / Tian XY
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32071192 China
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Structural insight into synergistic activation of human 3-methylcrotonyl-CoA carboxylase.
Authors: Jiayue Su / Xuyang Tian / Hang Cheng / Desheng Liu / Ziyi Wang / Shan Sun / Hong-Wei Wang / Sen-Fang Sui /
Abstract: The enzymes 3-methylcrotonyl-coenzyme A (CoA) carboxylase (MCC), pyruvate carboxylase and propionyl-CoA carboxylase belong to the biotin-dependent carboxylase family located in mitochondria. They ...The enzymes 3-methylcrotonyl-coenzyme A (CoA) carboxylase (MCC), pyruvate carboxylase and propionyl-CoA carboxylase belong to the biotin-dependent carboxylase family located in mitochondria. They participate in various metabolic pathways in human such as amino acid metabolism and tricarboxylic acid cycle. Many human diseases are caused by mutations in those enzymes but their structures have not been fully resolved so far. Here we report an optimized purification strategy to obtain high-resolution structures of intact human endogenous MCC, propionyl-CoA carboxylase and pyruvate carboxylase in different conformational states. We also determine the structures of MCC bound to different substrates. Analysis of MCC structures in different states reveals the mechanism of the substrate-induced, multi-element synergistic activation of MCC. These results provide important insights into the catalytic mechanism of the biotin-dependent carboxylase family and are of great value for the development of new drugs for the treatment of related diseases.
History
DepositionJun 30, 2023-
Header (metadata) releaseJul 3, 2024-
Map releaseJul 3, 2024-
UpdateMay 21, 2025-
Current statusMay 21, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36704.png

Downloads & links

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Map

FileDownload / File: emd_36704.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.97 Å/pix.
x 360 pix.
= 349.2 Å		0.97 Å/pix.
x 360 pix.
= 349.2 Å		0.97 Å/pix.
x 360 pix.
= 349.2 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.97 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.123
Minimum - Maximum-0.27829522 - 0.93563443
Average (Standard dev.)-0.0006573992 (±0.035780817)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 349.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36704_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36704_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Dodecamer of human MCC

EntireName: Dodecamer of human MCC
Components
  • Complex: Dodecamer of human MCC
    • Protein or peptide: Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial
    • Protein or peptide: Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial
  • Ligand: ~{S}-[2-[3-[[(2~{R})-4-[[[(2~{S},3~{S},4~{S},5~{S})-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]ethyl] 3-methylbut-2-enethioate
  • Ligand: 5-(HEXAHYDRO-2-OXO-1H-THIENO[3,4-D]IMIDAZOL-6-YL)PENTANAL

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Supramolecule #1: Dodecamer of human MCC

SupramoleculeName: Dodecamer of human MCC / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial

MacromoleculeName: Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial
type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO / EC number: methylcrotonoyl-CoA carboxylase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 61.406027 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MWAVLRLALR PCARASPAGP RAYHGDSVAS LGTQPDLGSA LYQENYKQMK ALVNQLHERV EHIKLGGGEK ARALHISRGK LLPRERIDN LIDPGSPFLE LSQFAGYQLY DNEEVPGGGI ITGIGRVSGV ECMIIANDAT VKGGAYYPVT VKKQLRAQEI A MQNRLPCI ...String:
MWAVLRLALR PCARASPAGP RAYHGDSVAS LGTQPDLGSA LYQENYKQMK ALVNQLHERV EHIKLGGGEK ARALHISRGK LLPRERIDN LIDPGSPFLE LSQFAGYQLY DNEEVPGGGI ITGIGRVSGV ECMIIANDAT VKGGAYYPVT VKKQLRAQEI A MQNRLPCI YLVDSGGAYL PRQADVFPDR DHFGRTFYNQ AIMSSKNIAQ IAVVMGSCTA GGAYVPAMAD ENIIVRKQGT IF LAGPPLV KAATGEEVSA EDLGGADLHC RKSGVSDHWA LDDHHALHLT RKVVRNLNYQ KKLDVTIEPS EEPLFPADEL YGI VGANLK RSFDVREVIA RIVDGSRFTE FKAFYGDTLV TGFARIFGYP VGIVGNNGVL FSESAKKGTH FVQLCCQRNI PLLF LQNIT GFMVGREYEA EGIAKDGAKM VAAVACAQVP KITLIIGGSY GAGNYGMCGR AYSPRFLYIW PNARISVMGG EQAAN VLAT ITKDQRAREG KQFSSADEAA LKEPIIKKFE EEGNPYYSSA RVWDDGIIDP ADTRLVLGLS FSAALNAPIE KTDFGI FRM

UniProtKB: Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial

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Macromolecule #2: Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial

MacromoleculeName: Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial
type: protein_or_peptide / ID: 2 / Number of copies: 6 / Enantiomer: LEVO / EC number: methylcrotonoyl-CoA carboxylase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 80.584016 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAASAVSVL LVAAERNRWH RLPSLLLPPR TWVWRQRTMK YTTATGRNIT KVLIANRGEI ACRVMRTAKK LGVQTVAVYS EADRNSMHV DMADEAYSIG PAPSQQSYLS MEKIIQVAKT SAAQAIHPGC GFLSENMEFA ELCKQEGIIF IGPPPSAIRD M GIKSTSKS ...String:
MAAASAVSVL LVAAERNRWH RLPSLLLPPR TWVWRQRTMK YTTATGRNIT KVLIANRGEI ACRVMRTAKK LGVQTVAVYS EADRNSMHV DMADEAYSIG PAPSQQSYLS MEKIIQVAKT SAAQAIHPGC GFLSENMEFA ELCKQEGIIF IGPPPSAIRD M GIKSTSKS IMAAAGVPVV EGYHGEDQSD QCLKEHARRI GYPVMIKAVR GGGGKGMRIV RSEQEFQEQL ESARREAKKS FN DDAMLIE KFVDTPRHVE VQVFGDHHGN AVYLFERDCS VQRRHQKIIE EAPAPGIKSE VRKKLGEAAV RAAKAVNYVG AGT VEFIMD SKHNFCFMEM NTRLQVEHPV TEMITGTDLV EWQLRIAAGE KIPLSQEEIT LQGHAFEARI YAEDPSNNFM PVAG PLVHL STPRADPSTR IETGVRQGDE VSVHYDPMIA KLVVWAADRQ AALTKLRYSL RQYNIVGLHT NIDFLLNLSG HPEFE AGNV HTDFIPQHHK QLLLSRKAAA KESLCQAALG LILKEKAMTD TFTLQAHDQF SPFSSSSGRR LNISYTRNMT LKDGKN NVA IAVTYNHDGS YSMQIEDKTF QVLGNLYSEG DCTYLKCSVN GVASKAKLII LENTIYLFSK EGSIEIDIPV PKYLSSV SS QETQGGPLAP MTGTIEKVFV KAGDKVKAGD SLMVMIAMKM EHTIKSPKDG TVKKVFYREG AQANRHTPLV EFEEEESD K RESE

UniProtKB: Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial

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Macromolecule #3: ~{S}-[2-[3-[[(2~{R})-4-[[[(2~{S},3~{S},4~{S},5~{S})-5-(6-aminopur...

MacromoleculeName: ~{S}-[2-[3-[[(2~{R})-4-[[[(2~{S},3~{S},4~{S},5~{S})-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxy-3,3-dimethyl-2-oxidanyl- ...Name: ~{S}-[2-[3-[[(2~{R})-4-[[[(2~{S},3~{S},4~{S},5~{S})-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]ethyl] 3-methylbut-2-enethioate
type: ligand / ID: 3 / Number of copies: 6 / Formula: TW3
Molecular weightTheoretical: 849.635 Da

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Macromolecule #4: 5-(HEXAHYDRO-2-OXO-1H-THIENO[3,4-D]IMIDAZOL-6-YL)PENTANAL

MacromoleculeName: 5-(HEXAHYDRO-2-OXO-1H-THIENO[3,4-D]IMIDAZOL-6-YL)PENTANAL
type: ligand / ID: 4 / Number of copies: 6 / Formula: BTI
Molecular weightTheoretical: 228.311 Da
Chemical component information

ChemComp-BTI:
5-(HEXAHYDRO-2-OXO-1H-THIENO[3,4-D]IMIDAZOL-6-YL)PENTANAL

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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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.3 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 82260
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: ANGULAR RECONSTITUTION

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