2nvc
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Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (3)
OverviewOverview
Human aldose reductase (ALR2) has evolved as a promising therapeutic, target for the treatment of diabetic long-term complications. The binding, site of this enzyme possesses two main subpockets: the catalytic, anion-binding site and the hydrophobic specificity pocket. The latter can, be observed in the open or closed state, depending on the bound ligand., Thus, it exhibits a pronounced capability for induced-fit adaptations, whereas the catalytic pocket exhibits rigid properties throughout all, known crystal structures. Here, we determined two ALR2 crystal structures, at 1.55 and 1.65 A resolution, each complexed with an inhibitor of the, recently described naphtho[1,2-d]isothiazole acetic acid series. In, contrast to the original design hypothesis based on the binding mode of, tolrestat (1), both inhibitors leave the specificity pocket in the closed, state. Unexpectedly, the more potent ligand (2) extends the catalytic, pocket by opening a novel subpocket. Access to this novel subpocket is, mainly attributed to the rotation of an indole moiety of Trp 20 by about, 35 degrees . The newly formed subpocket provides accommodation of the, naphthyl portion of the ligand. The second inhibitor, 3, differs from 2, only by an extended glycolic ester functionality added to one of its, carboxylic groups. However, despite this slight structural modification, the binding mode of 3 differs dramatically from that of the first, inhibitor, but provokes less pronounced induced-fit adaptations of the, binding cavity. Thus, a novel binding site conformation has been, identified in a region where previous complex structures suggested only, low adaptability of the binding pocket. Furthermore, the two ligand, complexes represent an impressive example of how the slight change of a, chemically extended side-chain at a given ligand scaffold can result in a, dramatically altered binding mode. In addition, our study emphasizes the, importance of crystal structure analysis for the translation of affinity, data into structure-activity relationships.
About this StructureAbout this Structure
2NVC is a Single protein structure of sequence from Homo sapiens with NAP and ITA as ligands. Active as Aldehyde reductase, with EC number 1.1.1.21 Full crystallographic information is available from OCA.
ReferenceReference
Evidence for a Novel Binding Site Conformer of Aldose Reductase in Ligand-Bound State., Steuber H, Zentgraf M, La Motta C, Sartini S, Heine A, Klebe G, J Mol Biol. 2007 Mar 15;. PMID:17418233
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