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- EMDB-61723: Structure of human IVD in complex with FAD and isovaleryl-CoA -

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Basic information

Entry
Database: EMDB / ID: EMD-61723
TitleStructure of human IVD in complex with FAD and isovaleryl-CoA
Map data
Sample
  • Complex: Homo tetramer of IVD in complex with FAD and isovaleryl-CoA
    • Protein or peptide: Isovaleryl-CoA dehydrogenase, mitochondrial
  • Ligand: Isovaleryl-coenzyme A
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
KeywordsIVD / FAD / Isovaleryl-CoA / HYDROLASE
Function / homology
Function and homology information


Isovaleric acidemia / isovaleryl-CoA dehydrogenase / 3-methylbutanoyl-CoA dehydrogenase activity / short-chain acyl-CoA dehydrogenase / L-leucine catabolic process / fatty acid beta-oxidation using acyl-CoA dehydrogenase / branched-chain amino acid catabolic process / Branched-chain amino acid catabolism / flavin adenine dinucleotide binding / mitochondrial matrix ...Isovaleric acidemia / isovaleryl-CoA dehydrogenase / 3-methylbutanoyl-CoA dehydrogenase activity / short-chain acyl-CoA dehydrogenase / L-leucine catabolic process / fatty acid beta-oxidation using acyl-CoA dehydrogenase / branched-chain amino acid catabolic process / Branched-chain amino acid catabolism / flavin adenine dinucleotide binding / mitochondrial matrix / mitochondrion / nucleoplasm / identical protein binding
Similarity search - Function
Isovaleryl-CoA dehydrogenase / Acyl-CoA dehydrogenases signature 1. / Acyl-CoA dehydrogenases signature 2. / Acyl-CoA dehydrogenase, conserved site / Acyl-CoA dehydrogenase/oxidase C-terminal / Acyl-CoA dehydrogenase/oxidase, N-terminal / Acyl-CoA dehydrogenase, N-terminal domain / Acyl-CoA dehydrogenase, C-terminal domain / Acyl-CoA oxidase/dehydrogenase, middle domain / Acyl-CoA dehydrogenase, middle domain ...Isovaleryl-CoA dehydrogenase / Acyl-CoA dehydrogenases signature 1. / Acyl-CoA dehydrogenases signature 2. / Acyl-CoA dehydrogenase, conserved site / Acyl-CoA dehydrogenase/oxidase C-terminal / Acyl-CoA dehydrogenase/oxidase, N-terminal / Acyl-CoA dehydrogenase, N-terminal domain / Acyl-CoA dehydrogenase, C-terminal domain / Acyl-CoA oxidase/dehydrogenase, middle domain / Acyl-CoA dehydrogenase, middle domain / Acyl-CoA dehydrogenase/oxidase, N-terminal domain superfamily / Acyl-CoA oxidase/dehydrogenase, middle domain superfamily / Acyl-CoA dehydrogenase/oxidase, N-terminal and middle domain superfamily / Acyl-CoA dehydrogenase-like, C-terminal
Similarity search - Domain/homology
Isovaleryl-CoA dehydrogenase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsJu K / Xu Y / Bai F / Luan X
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81902085 China
CitationJournal: Research (Wash D C) / Year: 2025
Title: Structural Insights into Isovaleryl-Coenzyme A Dehydrogenase: Mechanisms of Substrate Specificity and Implications of Isovaleric Acidemia-Associated Mutations.
Authors: Kaide Ju / Fang Bai / Youwei Xu / Qingao Li / Gengchen Su / Ye Jin / Houzao Chen / Shuyang Zhang / Xiaodong Luan /
Abstract: Isovaleryl-CoA (coenzyme A) dehydrogenase (IVD) plays a pivotal role in the catabolism of leucine, converting isovaleryl-CoA to 3-methylcrotonyl-CoA. Dysfunction of IVD is linked to isovaleric ...Isovaleryl-CoA (coenzyme A) dehydrogenase (IVD) plays a pivotal role in the catabolism of leucine, converting isovaleryl-CoA to 3-methylcrotonyl-CoA. Dysfunction of IVD is linked to isovaleric acidemia (IVA), a rare metabolic disorder characterized by the accumulation of toxic metabolites. In this study, we present the cryo-electron microscopy structures of human IVD, resolved both in its apo form and in complex with its substrates, isovaleryl-CoA and butyryl-CoA. Our findings reveal a tetrameric architecture with distinct substrate-binding pockets that facilitate the enzyme's preference for short branched-chain acyl-CoAs. Key residues involved in FAD binding and substrate interaction were identified, elucidating the catalytic mechanism of IVD. Additionally, we investigated the impact of various disease-associated hotspot mutations derived from different regions, demonstrating their effects on enzyme stability and activity. Notably, mutations such as A314V, S281G/F382V, and E411K resulted in substantial loss of function, while others exhibited milder effects, which is consistent with our structural analyses. These insights enhance our understanding of IVD's enzymatic properties and provide a foundation for developing targeted therapies for IVA.
History
DepositionSep 27, 2024-
Header (metadata) releaseJun 11, 2025-
Map releaseJun 11, 2025-
UpdateSep 10, 2025-
Current statusSep 10, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61723.png

Downloads & links

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Map

FileDownload / File: emd_61723.map.gz / Format: CCP4 / Size: 64 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.)
0.82 Å/pix.
x 256 pix.
= 210.944 Å		0.82 Å/pix.
x 256 pix.
= 210.944 Å		0.82 Å/pix.
x 256 pix.
= 210.944 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-1.4210993 - 2.0612645
Average (Standard dev.)0.005180386 (±0.068934254)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 210.944 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_61723_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_61723_half_map_2.map
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Sample components

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Entire : Homo tetramer of IVD in complex with FAD and isovaleryl-CoA

EntireName: Homo tetramer of IVD in complex with FAD and isovaleryl-CoA
Components
  • Complex: Homo tetramer of IVD in complex with FAD and isovaleryl-CoA
    • Protein or peptide: Isovaleryl-CoA dehydrogenase, mitochondrial
  • Ligand: Isovaleryl-coenzyme A
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE

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Supramolecule #1: Homo tetramer of IVD in complex with FAD and isovaleryl-CoA

SupramoleculeName: Homo tetramer of IVD in complex with FAD and isovaleryl-CoA
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isovaleryl-CoA dehydrogenase, mitochondrial

MacromoleculeName: Isovaleryl-CoA dehydrogenase, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: isovaleryl-CoA dehydrogenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.649668 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MAEMATATRL LGWRVASWRL RPPLAGFVSQ RAHSLLPVDD AINGLSEEQR QLRQTMAKFL QEHLAPKAQE IDRSNEFKNL REFWKQLGN LGVLGITAPV QYGGSGLGYL EHVLVMEEIS RASGAVGLSY GAHSNLCINQ LVRNGNEAQK EKYLPKLISG E YIGALAMS ...String:
MAEMATATRL LGWRVASWRL RPPLAGFVSQ RAHSLLPVDD AINGLSEEQR QLRQTMAKFL QEHLAPKAQE IDRSNEFKNL REFWKQLGN LGVLGITAPV QYGGSGLGYL EHVLVMEEIS RASGAVGLSY GAHSNLCINQ LVRNGNEAQK EKYLPKLISG E YIGALAMS EPNAGSDVVS MKLKAEKKGN HYILNGNKFW ITNGPDADVL IVYAKTDLAA VPASRGITAF IVEKGMPGFS TS KKLDKLG MRGSNTCELI FEDCKIPAAN ILGHENKGVY VLMSGLDLAR LVLAGGPLGL MQAVLDHTIP YLHVREAFGQ KIG HFQLMQ GKMADMYTRL MACRQYVYNV AKACDEGHCT AKDCAGVILY SAECATQVAL DGIQCFGGNG YINDFPMGRF LRDA KLYEI GAGTSEVRRL VIGRAFNADF H

UniProtKB: Isovaleryl-CoA dehydrogenase, mitochondrial

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Macromolecule #2: Isovaleryl-coenzyme A

MacromoleculeName: Isovaleryl-coenzyme A / type: ligand / ID: 2 / Number of copies: 4 / Formula: IVC
Molecular weightTheoretical: 851.651 Da
Chemical component information

ChemComp-IVC:
Isovaleryl-coenzyme A

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Macromolecule #3: FLAVIN-ADENINE DINUCLEOTIDE

MacromoleculeName: FLAVIN-ADENINE DINUCLEOTIDE / type: ligand / ID: 3 / Number of copies: 4 / Formula: FAD
Molecular weightTheoretical: 785.55 Da
Chemical component information

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM

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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: 7.4
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: 5.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 102113
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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