Paloma Vidal

Hevein Domains: An Attractive Model to Study Carbohydrate–Protein Interactions at Atomic Resolution

Publisher Summary This chapter focuses on hevein domains and presents an attractive model to study carbohydrate–protein interactions at atomic resolution. Among the various biological processes in which carbohydrates are involved as biochemical signals, it is noteworthy that many plants harbor defense proteins (lectins) against pathogenic attack. These proteins are able to bind to chitin. This natural biopolymer is a key structural component of the cell wall of fungi and of the exoskeleton of invertebrates such as insects, nematodes, and arthropods. Direct binding to the saccharide can occur for the respective lectin, while a particular domain can also be instrumental for chitin-degrading enzymes. The antifungal activity of plant chitinases is largely restricted to those chitinases that contain a noncatalytic, plant-specific, chitin-binding domain (ChBD), also termed as “hevein domain.” This domain displays a common structural motif of 30–43 residues, rich in glycine and cysteine residues in highly conserved positions and organized around a four-disulfide core. The chapter explains the concepts related to protein–carbohydrate interactions and elaborates the basic techniques for analyzing sugar–hevein interactions. It also discusses the structure of the Hevein–Saccharide complexes.

Conformational Selection in Glycomimetics: Human Galectin‐1 Only Recognizes syn‐Ψ‐Type Conformations of β‐1,3‐Linked Lactose and Its C‐Glycosyl Derivative

The human lectin galectin-1 (hGal-1) translates sugar signals, that is, β-galactosides, into effects on the level of cells, for example, growth regulation, and has become a model for studying binding of biopharmaceutically relevant derivatives. Bound-state conformations of Galβ-C-(1→3)-Glcβ-OMe (1) and its βGal-(1→3)-βGlc-OMe disaccharide parent compound were studied by using NMR spectroscopy (transferred (TR)-NOESY data), assisted by docking experiments and molecular dynamics (MD) simulations. The molecular recognition process involves a conformational selection event. Although free C-glycoside access four distinct conformers in solution, hGal-1 recognizes shape of a local minimum of compound 1, the syn-Φ/syn-Ψ conformer, not the structure at global minimum. MD simulations were run to explain, in structural terms, the observed geometry of the complex.

Preorganization of the Hydroxyethylene Dipeptide Isostere: The Preferred Conformation in Solution Resembles the Conformation Bound to BACE

Conformational analysis in solution of beta-secretase inhibitors 1 and 2 by NMR spectroscopy reveals that the hydroxyethylene isostere, an apparently flexible fragment widely used as a scissile bond replacement in aspartic protease inhibitors, exists in one predominant conformation in solution. This preferred conformation is similar to that adopted by the hydroxyethylene core of 1 in complex with beta-secretase and that adopted by hydroxyethylene cores of related compounds when bound to aspartic proteases, indicating that this structural unit is preorganized in solution.