The structure of human aldose reductase bound to the inhibitor IDD384

The crystallographic structure of the complex between human aldose reductas e (AR2) and one of its inhibitors, IDD384, has been solved at 1.7 Angstrom resolution from crystals obtained at pH 5.0. This structure shows that the binding of the inhibitor's hydrophilic head to the catalytic residues Tyr48 and His110 differs from that found previously with porcine AR2. The differ ence is attributed to a change in the protonation state of the inhibitor (p K(a) = 4.52) when soaked with crystals of human (at pH 5.0) or pig lens AR2 (at pH 6.2). This work demonstrates how strongly the detailed binding of t he inhibitor's polar head depends on its protonation state.