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

DI LELLA, SANTIAGO; CAPURRO, JUAN I. BLANCO; MODENUTTI, CARLOS P.; MARTÍ, MARCELO A.

Frontiers in Chemistry

Frontiers

Año: 2019 vol. 7

Galectins (formerly known as ?S-type lectins?) are a subfamily of soluble proteinsthat typically bind β-galactoside carbohydrates with high specificity. They are presentin many forms of life, from nematodes and fungi to animals, where they performa wide range of functions. Particularly in humans, different types of galectins havebeen described differing not only in their tissue expression but also in their cellularlocation, oligomerization, fold architecture and carbohydrate-binding affinity. This distinctyet sometimes overlapping distributions and physicochemical attributes make themresponsible for a wide variety of both intra- and extracellular functions, includingtremendous importance in immunity and disease. In this review, we aim to providea general description of galectins most important structural features, with a specialfocus on the molecular determinants of their carbohydrate-recognition ability. For thatpurpose, we structurally compare the human galectins, in light of recent mutagenesisstudies and novel X-ray structures. We also offer a detailed description on how touse the solvent structure surrounding the protein as a tool to get better predictionsof galectin-carbohydrate complexes, with a potential application to the rational designof glycomimetic inhibitory compounds. Finally, using Gal-1 and Gal-3 as paramountexamples, we review a series of recent advances in the development of engineeredgalectins and galectin inhibitors, aiming to dissect the structure-activity relationshipthrough the description of their interaction at the molecular level.