6R6U

Crystal structure of human cis-aconitate decarboxylase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.162 
  • R-Value Work: 0.145 
  • R-Value Observed: 0.146 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Crystal structure ofcis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis.

Chen, F.Lukat, P.Iqbal, A.A.Saile, K.Kaever, V.van den Heuvel, J.Blankenfeldt, W.Bussow, K.Pessler, F.

(2019) Proc Natl Acad Sci U S A 116: 20644-20654

  • DOI: https://doi.org/10.1073/pnas.1908770116
  • Primary Citation of Related Structures:  
    6R6T, 6R6U

  • PubMed Abstract: 

    cis -Aconitate decarboxylase (CAD, also known as ACOD1 or Irg1) converts cis -aconitate to itaconate and plays central roles in linking innate immunity with metabolism and in the biotechnological production of itaconic acid by Aspergillus terreus We have elucidated the crystal structures of human and murine CADs and compared their enzymological properties to CAD from A. terreus Recombinant CAD is fully active in vitro without a cofactor. Murine CAD has the highest catalytic activity, whereas Aspergillus CAD is best adapted to a more acidic pH. CAD is not homologous to any known decarboxylase and appears to have evolved from prokaryotic enzymes that bind negatively charged substrates. CADs are homodimers, the active center is located in the interface between 2 distinct subdomains, and structural modeling revealed conservation in zebrafish and Aspergillus We identified 8 active-site residues critical for CAD function and rare naturally occurring human mutations in the active site that abolished CAD activity, as well as a variant (Asn152Ser) that increased CAD activity and is common (allele frequency 20%) in African ethnicity. These results open the way for 1) assessing the potential impact of human CAD variants on disease risk at the population level, 2) developing therapeutic interventions to modify CAD activity, and 3) improving CAD efficiency for biotechnological production of itaconic acid.


  • Organizational Affiliation

    Department Structure and Function of Proteins, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cis-aconitate decarboxylase
A, B
462Homo sapiensMutation(s): 0 
Gene Names: ACOD1IRG1
EC: 4.1.1.6
UniProt & NIH Common Fund Data Resources
Find proteins for A6NK06 (Homo sapiens)
Explore A6NK06 
Go to UniProtKB:  A6NK06
PHAROS:  A6NK06
GTEx:  ENSG00000102794 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA6NK06
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BU3
Query on BU3

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B],
H [auth B],
I [auth B]
(R,R)-2,3-BUTANEDIOL
C4 H10 O2
OWBTYPJTUOEWEK-QWWZWVQMSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
J [auth B]
K [auth B]
D [auth A],
E [auth A],
F [auth A],
J [auth B],
K [auth B],
L [auth B]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CSD
Query on CSD
A, B
L-PEPTIDE LINKINGC3 H7 N O4 SCYS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.162 
  • R-Value Work: 0.145 
  • R-Value Observed: 0.146 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.01α = 90
b = 109.98β = 90
c = 74.974γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-09-25
    Type: Initial release
  • Version 1.1: 2019-10-02
    Changes: Data collection, Database references
  • Version 1.2: 2019-10-16
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-24
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.4: 2024-11-06
    Changes: Structure summary