The Structural Biology of Galectin-Ligand Recognition: Current Advances in Modeling Tools, Protein Engineering, and Inhibitor Design

Abstract

Galectins (formerly known as “S-type lectins”) are a subfamily of soluble proteins that typically bind β-galactoside carbohydrates with high specificity. They are present in many forms of life, from nematodes and fungi to animals, where they perform a wide range of functions. Particularly in humans, different types of galectins have been described differing not only in their tissue expression but also in their cellular location, oligomerization, fold architecture and carbohydrate-binding affinity. This distinct yet sometimes overlapping distributions and physicochemical attributes make them responsible for a wide variety of both intra- and extracellular functions, including tremendous importance in immunity and disease. In this review, we aim to provide a general description of galectins most important structural features, with a special focus on the molecular determinants of their carbohydrate-recognition ability. For that purpose, we structurally compare the human galectins, in light of recent mutagenesis studies and novel X-ray structures. We also offer a detailed description on how to use the solvent structure surrounding the protein as a tool to get better predictions of galectin-carbohydrate complexes, with a potential application to the rational design of glycomimetic inhibitory compounds. Finally, using Gal-1 and Gal-3 as paramount examples, we review a series of recent advances in the development of engineered galectins and galectin inhibitors, aiming to dissect the structure-activity relationship through the description of their interaction at the molecular level.

An egg-derived sulfated N-Acetyllactosamine glycan is an antigenic decoy of influenza virus vaccines

“…the Lewis blood group determinants (32,33). LacNAcs are also the main ligand for galectins and mediate a variety of cellular functions including cell adhesion, migration, proliferation, and apoptosis (34)(35)(36).…”

Binding of CML-Modified as Well as Heat-Glycated β-lactoglobulin to Receptors for AGEs Is Determined by Charge and Hydrophobicity

“…Moreover, the role of charge in binding to murine CD36 ectodomain has also been postulated for diacylglycerol ligands [ 47 ], thus supporting the hypothesis that also for CD36 the negatively charged CML moiety of BLG-CML is essential for binding to the receptor. Galectins in general bind to carbohydrates, which is considered to occur as a result of hydrophilic interactions via hydrogen bonds, and hydrophobic interactions, specifically the CH-π interaction [ 48 ]. This explains the binding affinity of galectin-3 to lectins and lipopolysaccharides but not to BLG-CML with the hypothesis of a charge-dependent recognition.…”

Functional reprogramming of Candida glabrata epithelial adhesins: the role of conserved and variable structural motifs in ligand binding

“…2). However, functionally analogous tryptophans are highly conserved in the binding pockets of PA14/Flo5 adhesins of the glabrata group of Nakaseomyces yeasts and also in structurally unrelated carbohydrate binding sites of galectins, which typically bind galactosides with high specificity (27). Replacements to other aromatics like tyrosine are only found for few Epa1-like adhesins, e.g.…”