Tobias Hüfner

Human aldose reductase, a target for the development of inhibitors for preventing diabetic complications, displays a transient specificity pocket which opens upon binding with specific, potent inhibitors. We investigated the opening mechanism of this pocket by mutating leucine residues involved in the gate keeping mechanism to alanine. Two isostructural inhibitors distinguished only by a single nitro to carboxy group replacement, have a 1000‐fold difference in their binding affinity to the wild type. This difference is reduced to 10‐fold in the mutated variants as the nitro derivative loses in affinity but conserves binding to the open transient pocket. The affinity of the carboxylate analog is minimally altered but the analog binding preference changes from the closed to open state of the transient pocket. Differences in the solvation properties of ligands and the transient pocket as well as changes from induced fit to conformational selections provide an explanation for the altered behavior of the ligands with respect to their binding to the different variants.