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

Abstract

The first structure of an aldehyde dehydrogenase (ALDH) is described at 2.6 Å 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 Å long funnel-shaped passage with a 6 x 12 Å opening leading to a putative catalytic pocket. A new mode of nad binding, which differs substantially from the classic β-α-β binding mode associated with the 'Rossmann fold', is observed which we term the β-α,β 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.