Adherence to Bürgi–Dunitz stereochemical principles requires significant structural rearrangements in Schiff-base formation: insights from transaldolase complexes

Light, S.H.; Minasov, G.; Duban, M.-E.; Anderson, W.F.

doi:10.1107/S1399004713030666

Figure 2
Categories of conformational change that could accompany Schiff-base formation within an active site. The nucleophilic approach of the lysine N^∊ atom to a substrate carbonyl is predicted to follow an obtuse α_BD (see Fig. 1

). (a) Pre-nucleophilic attack state. The substrate forms an initial interaction with the enzyme that positions its carbonyl at an appropriate α_BD relative to the lysine N^∊ atom. For the N^∊ atom to assume an obtuse α_BD but ultimately represent a component of the Schiff base, it follows that >90° of angular rotation must occur in the intervening bond formation. Three categories of positional/conformational change could occur individually or in combination to achieve this rotation. (b) Rigid enzyme, rigid substrate. In this case, the conformations of main/side chains of the enzyme do not change from the pre-nucleophilic attack state positions, but the overall position of the substrate changes via gross rotation toward the lysine N^∊ atom, without significant change to internal substrate dihedral angles. (c) Flexible enzyme, rigid substrate. The position and internal dihedrals of the substrate do not change from their pre-nucleophilic attack state values, but significant protein conformational change results in movement of the lysine N^∊ atom toward the plane of the substrate carbonyl. (d) Rigid enzyme, flexible substrate. The conformation of the enzyme and the gross position of the substrate do not change, but a significant substrate conformational change (change in internal dihedrals) results in rotation of the plane of the substrate carbonyl towards the lysine N^∊ atom. Within the schematic representation, the substructures of the carbonyl substrate, R₁C(O)R₂, are represented by the maroon ribbon, with internal conformational change indicated by a twist in the ribbon. The active site with its reactive lysine is represented within the dark blue body and ledge.

BIOLOGICAL
CRYSTALLOGRAPHY

ISSN: 1399-0047

Volume 70| Part 2| January 2014| Pages 544-552

doi:10.1107/S1399004713030666

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