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- PDB-9jq5: Structure of human IVD in complex with FAD and isovaleryl-CoA -

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Basic information

Entry
Database: PDB / ID: 9jq5
TitleStructure of human IVD in complex with FAD and isovaleryl-CoA
ComponentsIsovaleryl-CoA dehydrogenase, mitochondrial
KeywordsHYDROLASE / IVD / FAD / Isovaleryl-CoA
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
FLAVIN-ADENINE DINUCLEOTIDE / Isovaleryl-coenzyme A / Isovaleryl-CoA dehydrogenase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsJu, K. / Xu, Y. / Bai, F. / Luan, X.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 10, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.page_last / _citation.pdbx_database_id_PubMed ..._citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isovaleryl-CoA dehydrogenase, mitochondrial
B: Isovaleryl-CoA dehydrogenase, mitochondrial
C: Isovaleryl-CoA dehydrogenase, mitochondrial
D: Isovaleryl-CoA dehydrogenase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)193,14712
Polymers186,5994
Non-polymers6,5498
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Isovaleryl-CoA dehydrogenase, mitochondrial / IVD / Butyryl-CoA dehydrogenase


Mass: 46649.668 Da / Num. of mol.: 4 / Mutation: E286A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IVD / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P26440, isovaleryl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase
#2: Chemical
ChemComp-IVC / Isovaleryl-coenzyme A / S-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-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-methylbutanethioate


Mass: 851.651 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H44N7O17P3S
#3: Chemical
ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
Has ligand of interestN
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: Homo tetramer of IVD in complex with FAD and isovaleryl-CoA
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.4
SpecimenEmbedding 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 / Nominal defocus max: 5000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 102113 / Symmetry type: POINT

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