|Entry||Database: PDB / ID: 6o4l|
|Title||Structure of ALDH7A1 mutant E399D complexed with NAD|
|Components||Alpha-aminoadipic semialdehyde dehydrogenase|
|Keywords||OXIDOREDUCTASE / ALDEHYDE DEHYDROGENASE / NAD / LYSINE CATABOLISM|
|Function / homology|
Function and homology information
L-aminoadipate-semialdehyde dehydrogenase / L-aminoadipate-semialdehyde dehydrogenase activity / Choline catabolism / choline catabolic process / betaine-aldehyde dehydrogenase / betaine-aldehyde dehydrogenase activity / glycine betaine biosynthetic process from choline / Lysine catabolism / cellular aldehyde metabolic process / glyceraldehyde-3-phosphate dehydrogenase (NAD+) (non-phosphorylating) activity ...L-aminoadipate-semialdehyde dehydrogenase / L-aminoadipate-semialdehyde dehydrogenase activity / Choline catabolism / choline catabolic process / betaine-aldehyde dehydrogenase / betaine-aldehyde dehydrogenase activity / glycine betaine biosynthetic process from choline / Lysine catabolism / cellular aldehyde metabolic process / glyceraldehyde-3-phosphate dehydrogenase (NAD+) (non-phosphorylating) activity / aldehyde dehydrogenase (NAD+) / aldehyde dehydrogenase (NAD+) activity / sensory perception of sound / mitochondrial matrix / mitochondrion / extracellular exosome / identical protein binding / nucleus / cytosol
Similarity search - Function
Aldehyde dehydrogenase family 7 member A1-like / Aldehyde Dehydrogenase; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 1 / Aldehyde Dehydrogenase; Chain A, domain 1 / Aldehyde dehydrogenases glutamic acid active site. / Aldehyde dehydrogenase, glutamic acid active site / Aldehyde dehydrogenase domain / Aldehyde dehydrogenase family / Aldehyde dehydrogenase, C-terminal ...Aldehyde dehydrogenase family 7 member A1-like / Aldehyde Dehydrogenase; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 1 / Aldehyde Dehydrogenase; Chain A, domain 1 / Aldehyde dehydrogenases glutamic acid active site. / Aldehyde dehydrogenase, glutamic acid active site / Aldehyde dehydrogenase domain / Aldehyde dehydrogenase family / Aldehyde dehydrogenase, C-terminal / Aldehyde dehydrogenase, N-terminal / Aldehyde/histidinol dehydrogenase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Alpha-aminoadipic semialdehyde dehydrogenase
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||X-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.85 Å|
|Authors||Tanner, J.J. / Korasick, D.A. / Laciak, A.R.|
|Funding support|| United States, 1items |
|Citation||Journal: J Inherit Metab Dis / Year: 2020|
Title: Structural analysis of pathogenic mutations targeting Glu427 of ALDH7A1, the hot spot residue of pyridoxine-dependent epilepsy.
Authors: Adrian R Laciak / David A Korasick / Kent S Gates / John J Tanner /
Abstract: Certain loss-of-function mutations in the gene encoding the lysine catabolic enzyme aldehyde dehydrogenase 7A1 (ALDH7A1) cause pyridoxine-dependent epilepsy (PDE). Missense mutations of Glu427, ...Certain loss-of-function mutations in the gene encoding the lysine catabolic enzyme aldehyde dehydrogenase 7A1 (ALDH7A1) cause pyridoxine-dependent epilepsy (PDE). Missense mutations of Glu427, especially Glu427Gln, account for ~30% of the mutated alleles in PDE patients, and thus Glu427 has been referred to as a mutation hot spot of PDE. Glu427 is invariant in the ALDH superfamily and forms ionic hydrogen bonds with the nicotinamide ribose of the NAD cofactor. Here we report the first crystal structures of ALDH7A1 containing pathogenic mutations targeting Glu427. The mutant enzymes E427Q, Glu427Asp, and Glu427Gly were expressed in Escherichia coli and purified. The recombinant enzymes displayed negligible catalytic activity compared to the wild-type enzyme. The crystal structures of the mutant enzymes complexed with NAD were determined to understand how the mutations impact NAD binding. In the E427Q and E427G structures, the nicotinamide mononucleotide is highly flexible and lacks a defined binding pose. In E427D, the bound NAD adopts a "retracted" conformation in which the nicotinamide ring is too far from the catalytic Cys residue for hydride transfer. Thus, the structures revealed a shared mechanism for loss of function: none of the variants are able to stabilise the nicotinamide of NAD in the pose required for catalysis. We also show that these mutations reduce the amount of active tetrameric ALDH7A1 at the concentration of NAD tested. Altogether, our results provide the three-dimensional molecular structural basis of the most common pathogenic variants of PDE and implicate strong (ionic) hydrogen bonds in the aetiology of a human disease.
|Structure viewer||Molecule: |
Downloads & links
A: Alpha-aminoadipic semialdehyde dehydrogenase
B: Alpha-aminoadipic semialdehyde dehydrogenase
C: Alpha-aminoadipic semialdehyde dehydrogenase
D: Alpha-aminoadipic semialdehyde dehydrogenase
Mass: 55606.340 Da / Num. of mol.: 4 / Mutation: E399D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALDH7A1, ATQ1 / Production host: Escherichia coli (E. coli)
References: UniProt: P49419, L-aminoadipate-semialdehyde dehydrogenase, aldehyde dehydrogenase (NAD+), betaine-aldehyde dehydrogenase
|#3: Chemical||#4: Chemical|
Mass: 663.425 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
|#5: Water|| ChemComp-HOH / |
|Experiment||Method: X-RAY DIFFRACTION / Number of used crystals: 1|
|Crystal||Density Matthews: 2.03 Å3/Da / Density % sol: 39.47 %|
|Crystal grow||Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.7 |
Details: 0.2 M MgCl2, 21% (w/v) PEG 3350, and 0.1 M Bis-Tris pH 5.7
|Diffraction||Serial crystal experiment: N|
|Diffraction source||Source: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1 Å|
|Detector||Type: RDI CMOS_8M / Detector: CMOS / Date: May 29, 2018|
|Radiation||Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray|
|Radiation wavelength||Wavelength: 1 Å / Relative weight: 1|
|Reflection||Resolution: 1.85→45.72 Å / Num. obs: 149120 / % possible obs: 98.7 % / Redundancy: 10 % / CC1/2: 0.999 / Rmerge(I) obs: 0.104 / Rpim(I) all: 0.034 / Rrim(I) all: 0.11 / Net I/σ(I): 16.7 / Num. measured all: 1488879 / Scaling rejects: 354|
|Refinement||Method to determine structure: FOURIER SYNTHESIS|
Starting model: 4zuk
Resolution: 1.85→45.72 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 0.31 / Phase error: 24.81
|Solvent computation||Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å|
|Displacement parameters||Biso max: 98.3 Å2 / Biso mean: 36.0412 Å2 / Biso min: 13.32 Å2|
|Refinement step||Cycle: final / Resolution: 1.85→45.72 Å|
|LS refinement shell|
Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30
|Refinement TLS params.|
Method: refined / Refine-ID: X-RAY DIFFRACTION
|Refinement TLS group|
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