PDBsum entry 1ag8

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Oxidoreductase PDB id
Protein chains
493 a.a. *
Waters ×140
* Residue conservation analysis

References listed in PDB file
Key reference
Title Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion.
Authors C.G.Steinmetz, P.Xie, H.Weiner, T.D.Hurley.
Ref. Structure, 1997, 5, 701-711. [DOI no: 10.1016/S0969-2126(97)00224-4]
PubMed id 9195888
Note In the PDB file this reference is annotated as "TO BE PUBLISHED". The citation details given above were identified by an automated search of PubMed on title and author names, giving a percentage match of 0%.
BACKGROUND: The single genetic factor most strongly correlated with reduced alcohol consumption and incidence of alcoholism is a naturally occurring variant of mitochondrial aldehyde dehydrogenase (ALDH2). This variant contains a glutamate to lysine substitution at position 487 (E487K). The E487K variant of ALDH2 is found in approximately 50% of the Asian population, and is associated with a phenotypic loss of ALDH2 activity in both heterozygotes and homozygotes. ALDH2-deficient individuals exhibit an averse response to ethanol consumption, which is probably caused by elevated levels of blood acetaldehyde. The structure of ALDH2 is important for the elucidation of its catalytic mechanism, to gain a clear understanding of the contribution of ALDH2 to the genetic component of alcoholism and for the development of specific ALDH2 inhibitors as potential drugs for use in the treatment of alcoholism. RESULTS: The X-ray structure of bovine ALDH2 has been solved to 2.65 A in its free form and to 2.75 A in a complex with NAD+. The enzyme structure contains three domains; two dinucleotide-binding domains and a small three-stranded beta-sheet domain, which is involved in subunit interactions in this tetrameric enzyme. The E487K mutation occurs in this small oligomerization domain and is located at a key interface between subunits immediately below the active site of another monomer. The active site of ALDH2 is divided into two halves by the nicotinamide ring of NAD+. Adjacent to the A-side (Pro-R) of the nicotinamide ring is a cluster of three cysteines (Cys301, Cys302 and Cys303) and adjacent to the B-side (Pro-S) are Thr244, Glu268, Glu476 and an ordered water molecule bound to Thr244 and Glu476. CONCLUSIONS: Although there is a recognizable Rossmann-type fold, the coenzyme-binding region of ALDH2 binds NAD+ in a manner not seen in other NAD+-binding enzymes. The positions of the residues near the nicotinamide ring of NAD+ suggest a chemical mechanism whereby Glu268 functions as a general base through a bound water molecule. The sidechain amide nitrogen of Asn169 and the peptide nitrogen of Cys302 are in position to stabilize the oxyanion present in the tetrahedral transition state prior to hydride transfer. The functional importance of residue Glu487 now appears to be due to indirect interactions of this residue with the substrate-binding site via Arg264 and Arg475.
Figure 5.
Figure 5. Interactions between the enzyme and the bound cofactor from a single subunit in ALDH2. The bound NAD^+ molecule is shown using a ball-and-stick representation and colored according to atom type. Dashed lines indicate potential hydrogen-bonding interactions <3.3 , except for the interaction between the peptide nitrogen of Trp168 and the nicotinamide phosphate which is 3.6 (see text). (Figure was produced using the program MOLSCRIPT [52].)
The above figure is reprinted by permission from Cell Press: Structure (1997, 5, 701-711) copyright 1997.
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