6O4H

Structure of ALDH7A1 mutant A171V complexed with NAD


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.177 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural and biochemical consequences of pyridoxine-dependent epilepsy mutations that target the aldehyde binding site of aldehyde dehydrogenase ALDH7A1.

Laciak, A.R.Korasick, D.A.Wyatt, J.W.Gates, K.S.Tanner, J.J.

(2020) FEBS J 287: 173-189

  • DOI: https://doi.org/10.1111/febs.14997
  • Primary Citation of Related Structures:  
    6O4B, 6O4C, 6O4D, 6O4E, 6O4F, 6O4G, 6O4H

  • PubMed Abstract: 

    In humans, certain mutations in the gene encoding aldehyde dehydrogenase 7A1 are associated with pyridoxine-dependent epilepsy (PDE). Understanding the impact of PDE-causing mutations on the structure and activity of ALDH7A1 could allow for the prediction of symptom-severity and aid the development of patient-specific medical treatments. Herein, we investigate the biochemical and structural consequences of PDE missense mutations targeting residues in the aldehyde substrate binding site: N167S, P169S, A171V, G174V, and W175G. All but G174V could be purified for biochemical and X-ray crystallographic analysis. W175G has a relatively mild kinetic defect, exhibiting a fivefold decrease in k cat with no change in K m . P169S and N167S have moderate defects, characterized by catalytic efficiencies of 20- and 100-times lower than wild-type, respectively. A171V has a profound functional defect, with catalytic efficiency 2000-times lower than wild-type. The crystal structures of the variants are the first for any PDE-associated mutant of ALDH7A1. The structures show that missense mutations that decrease the steric bulk of the side chain tend to create a cavity in the active site. The protein responds by relaxing into the vacant space, and this structural perturbation appears to cause misalignment of the aldehyde substrate in W175G and N167S. The P169S structure is nearly identical to that of the wild-type enzyme; however, analysis of B-factors suggests the catalytic defect may result from altered protein dynamics. The A171V structure suggests that the potential for steric clash with Val171 prevents Glu121 from ion pairing with the amino group of the aldehyde substrate. ENZYMES: Aldehyde dehydrogenase 7A1 (EC1.2.1.31). DATABASES: Coordinates have been deposited in the Protein Data Bank under the following accession codes: 6O4B, 6O4C, 6O4D, 6O4E, 6O4F, 6O4G, 6O4H.


  • Organizational Affiliation

    Department of Chemistry, University of Missouri, Columbia, MO, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Alpha-aminoadipic semialdehyde dehydrogenase
A, B, C, D, E
A, B, C, D, E, F, G, H
513Homo sapiensMutation(s): 1 
Gene Names: ALDH7A1ATQ1
EC: 1.2.1.31 (PDB Primary Data), 1.2.1.3 (PDB Primary Data), 1.2.1.8 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P49419 (Homo sapiens)
Explore P49419 
Go to UniProtKB:  P49419
PHAROS:  P49419
GTEx:  ENSG00000164904 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49419
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAD (Subject of Investigation/LOI)
Query on NAD

Download Ideal Coordinates CCD File 
I [auth A]
K [auth B]
L [auth C]
M [auth D]
N [auth E]
I [auth A],
K [auth B],
L [auth C],
M [auth D],
N [auth E],
P [auth F],
Q [auth G],
R [auth H]
NICOTINAMIDE-ADENINE-DINUCLEOTIDE
C21 H27 N7 O14 P2
BAWFJGJZGIEFAR-NNYOXOHSSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
J [auth B],
O [auth F]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.177 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 155.978α = 90
b = 161.361β = 95
c = 159.161γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR01GM093123

Revision History  (Full details and data files)

  • Version 1.0: 2019-07-24
    Type: Initial release
  • Version 1.1: 2020-01-01
    Changes: Author supporting evidence
  • Version 1.2: 2020-01-15
    Changes: Database references
  • Version 1.3: 2023-10-11
    Changes: Data collection, Database references, Refinement description