5J5Z

Crystal structure of the D444V disease-causing mutant of the human dihydrolipoamide dehydrogenase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.84 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Crystal structures of the disease-causing D444V mutant and the relevant wild type human dihydrolipoamide dehydrogenase.

Szabo, E.Mizsei, R.Wilk, P.Zambo, Z.Torocsik, B.Weiss, M.S.Adam-Vizi, V.Ambrus, A.

(2018) Free Radic Biol Med 124: 214-220

  • DOI: https://doi.org/10.1016/j.freeradbiomed.2018.06.008
  • Primary Citation of Related Structures:  
    5J5Z, 5NHG

  • PubMed Abstract: 

    We report the crystal structures of the human (dihydro)lipoamide dehydrogenase (hLADH, hE3) and its disease-causing homodimer interface mutant D444V-hE3 at 2.27 and 1.84 Å resolution, respectively. The wild type structure is a unique uncomplexed, unliganded hE3 structure with the true canonical sequence. Based on the structural information a novel molecular pathomechanism is proposed for the impaired catalytic activity and enhanced capacity for reactive oxygen species generation of the pathogenic mutant. The mechanistic model involves a previously much ignored solvent accessible channel leading to the active site that might be perturbed also by other disease-causing homodimer interface substitutions of this enzyme.


  • Organizational Affiliation

    Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, Semmelweis University, H-1094 Budapest, Hungary.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydrolipoyl dehydrogenase, mitochondrial
A, B
496Homo sapiensMutation(s): 1 
Gene Names: DLDGCSLLADPHE3
EC: 1.8.1.4
UniProt & NIH Common Fund Data Resources
Find proteins for P09622 (Homo sapiens)
Explore P09622 
Go to UniProtKB:  P09622
PHAROS:  P09622
GTEx:  ENSG00000091140 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09622
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.84 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 118.035α = 90
b = 168.939β = 90
c = 61.279γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MxCuBEdata collection
XDSdata reduction
XDSdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Hungarian Academy of Sciences (MTA)Hungary02001
Hungarian Scientific Research Fund (OTKA)Hungary112230
Hungarian Brain Research Program (NAP)HungaryKTIA_13_NAP_A_III/6
European Molecular Biology OrganizationHungaryShort-term Fellowship [to A.A.]
Hungarian Academy of SciencesHungaryBolyai Fellowship [to A.A]

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-15
    Type: Initial release
  • Version 1.1: 2018-03-28
    Changes: Source and taxonomy
  • Version 1.2: 2018-07-04
    Changes: Data collection, Database references, Derived calculations
  • Version 1.3: 2018-07-11
    Changes: Data collection, Database references
  • Version 1.4: 2024-01-10
    Changes: Data collection, Database references, Refinement description