The first structure of an aldehyde dehydrogenase reveals novel interactions between NAD and the Rossmann fold

The first structure of an aldehyde dehydrogenase (ALDH) is described at 2.6 Angstrom resolution. Each subunit of the dimeric enzyme contains an NAD-binding domain, a catalytic domain and a bridging domain. At the interface of these domains is a 15 Angstrom long funnel-shaped passage with a 6 x 12 Angstrom opening leading to a putative catalytic pocket. A new mode of NAD binding, which differs substantially from the classic beta-alpha-beta binding mode associated with the 'Rossmann fold', is observed which we term the beta-alpha,beta mode. Sequence comparisons of the class 3 ALDH with other ALDHs indicate a similar polypeptide fold, novel NAD-binding mode and catalytic site for this family. A mechanism for enzymatic specificity and activity is postulated.